Heteroaryl 11-beta-hydroxysteroid dehydrogenase type I inhibitors

ABSTRACT

Novel compounds are provided which are 11-beta-hydroxysteroid dehydrogenase type I inhibitors. 11-beta-hydroxysteroid dehydrogenase type I inhibitors are useful in treating, preventing, or slowing the progression of diseases requiring 11-beta-hydroxysteroid dehydrogenase type I inhibitor therapy. These novel compounds have the structure:
 
W-L-Z  (I)
 
or stereoisomers or prodrugs or pharmaceutically acceptable salts thereof, wherein W, L and Z are defined herein.

This application claims the benefit of U.S. Provisional Application No.60/688,993, filed Jun. 9, 2005, incorporated herein by reference in itsentirety.

BACKGROUND OF THE INVENTION

The steroid hormone cortisol is a key regulator of many physiologicalprocesses. However, an excess of cortisol, as occurs in Cushing'sDisease, provokes severe metabolic abnormalities including: type 2diabetes, cardiovascular disease, obesity, and osteoporosis. Manypatients with these diseases, however, do not show significant increasesin plasma cortisol levels. In addition to plasma cortisol, individualtissues can regulate their glucocorticoid tone via the in situconversion of inactive cortisone to the active hormone cortisol. Indeed,the normally high plasma concentration of cortisone provides a readysupply of precursor for conversion to cortisol via the intracellularenzyme 11-beta-hydroxysteroid dehydrogenase type I (11beta-HSD1).

11beta-HSD1 is a member of the short chain dehydrogenase superfamily ofenzymes. By catalyzing the conversion of cortisone to cortisol,11beta-HSD1 controls the intracellular glucocorticoid tone according toits expression and activity levels. In this manner, 11beta-HSD1 candetermine the overall metabolic status of the organ. 11beta-HSD1 isexpressed at high levels in the liver and at lower levels in manymetabolically active tissues including the adipose, the CNS, thepancreas, and the pituitary. Taking the example of the liver, it ispredicted that high levels of 11beta-HSD1 activity will stimulategluconeogenesis and overall glucose output. Conversely, reduction of11beta-HSD1 activity will downregulate gluconeogenesis resulting inlower plasma glucose levels.

Various studies have been conducted that support this hypothesis. Forexample, transgenic mice expressing 2× the normal level of 11beta-HSD1in only the adipose tissue show abdominal obesity, hyperglycemia, andinsulin resistance. (H. Masuzaki, J. Paterson, H. Shinyama, N. M.Morton, J. J. Mullins, J. R. Seckl, J. S. Flier, A Transgenic Model ofVisceral Obesity and the Metabolic Syndrome, Science 294:2166-2170(2001). Conversely, when the 11beta-HSD1 gene is ablated by homologousrecombination, the resulting mice are resistant to diet induced obesityand the accompanying dysregulation of glucose metabolism (N. M. Morton,J. M. Paterson, H. Masuzki, M. C. Holmes, B. Staels, C. Fievet, B. R.Walker, J. S. Flier, J. J. Mullings, J. R. Seckl, Novel AdiposeTissue-Mediated Resistance to Diet-induced Visceral Obesity in11β-Hydroxysteroid Dehydrogenase Type 1-Deficient Mice. Diabetes 53:931-938 (2004). In addition, treatment of genetic mouse models ofobesity and diabetes (ob/ob, db/db and KKAy mice) with a specificinhibitor of 11beta-HSD1 causes a decrease in glucose output from theliver and an overall increase in insulin sensitivity (P. Alberts, C.Nilsson, G. Selen, L. O. M. Engblom, N. H. M. Edling, S. Norling, G.Klingstrom, C. Larsson, M. Forsgren, M. Ashkzari, C. E. Nilsson, M.Fiedler, E. Bergqvist, B. Ohman, E. Bjorkstrand, L. B. Abrahmsen,Selective Inhibition of 11β-Hydroxysteroid Dehydrogenase Type I ImprovesHepatic Insuling Sensuitivity in Hyperglycemic Mice Strains,Endocrinology 144: 4755-4762 (2003)). Furthermore, inhibitors of11beta-HSD1 have been shown to be effective in treating metabolicsyndrome and atherosclerosis in high fat fed mice (Hermanowoki-Vosetkaet. al., J. Eg. Med., 2002, 202(4), 517-527). Based in part on thesestudies, it is believed that local control of cortisol levels isimportant in metabolic diseases in these model systems. In addition, theresults of these studies also suggest that inhibition of 11beta-HSD1will be a viable strategy for treating metabolic diseases such as type 2diabetes, obesity, and the metabolic syndrome.

Lending further support to this idea are the results of a series ofpreliminary clinical studies. For example, several reports have shownthat adipose tissue from obese individuals has elevated levels of11beta-HSD1 activity. In addition, studies with carbenoxolone, a naturalproduct derived from licorice that inhibits both 11beta-HSD1 and11beta-HSD2 (converts cortisol to cortisone in kidney) have shownpromising results. A seven day, double blind, placebo controlled, crossover study with carbenoxolone in mildly overweight individuals with type2 diabetes showed that patients treated with the inhibitor, but not theplacebo group, displayed a decrease in hepatic glucose production (R. C.Andrews, O. Rooyackers, B. R. Walker, J. Clin. Endocrinol. Metab. 88:285-291 (2003)). This observation is consistent with the inhibition of11beta-HSD1 in the liver. The results of these preclinical and earlyclinical studies strongly support the concept that treatment with apotent and selective inhibitor of 11beta-HSD1 will be an efficacioustherapy in patients afflicted with type 2 diabetes, obesity, and themetabolic syndrome.

SUMMARY OF THE INVENTION

In accordance with the present invention, aryl and heteroaryl andrelated compounds are provided that have the general structure offormula I:W-L-Z  (I)wherein W, L and Z are defined below.

The compounds of the present invention inhibit the activity of theenzyme 11-beta-hydroxysteroid dehydrogenase type I. Consequently, thecompounds of the present invention may be used in the treatment ofmultiple diseases or disorders associated with 11-beta-hydroxysteroiddehydrogenase type I, such as diabetes and related conditions,microvascular complications associated with diabetes, the macrovascularcomplications associated with diabetes, cardiovascular diseases,Metabolic Syndrome and its component conditions, inflammatory diseasesand other maladies. Examples of diseases or disorders associated withthe activity of the enzyme 11-beta-hydroxysteroid dehydrogenase type Ithat can be prevented, inhibited, or treated according to the presentinvention include, but are not limited to, diabetes, hyperglycemia,impaired glucose tolerance, insulin resistance, hyperinsulinemia,retinopathy, neuropathy, nephropathy, delayed wound healing,atherosclerosis and its sequelae (acute coronary syndrome, myocardialinfarction, angina pectoris, peripheral vascular disease, intermitantclaudication), abnormal heart function, myocardial ischemia, stroke,Metabolic Syndrome, hypertension, obesity, dislipidemia, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL,non-cardiac ischemia, infection, cancer, vascular restenosis,pancreatitis, neurodegenerative disease, lipid disorders, cognitiveimpairment and dementia, bone disease, HIV protease associatedlipodystrophy, glaucoma and inflammatory diseases, such as, rheumatoidarthritis and osteoarthritis.

Inhibitors of 11 beta-HSD1 are also described in U.S. patent applicationSer. No. 11/448,947, titled “Triazolopyridine 11-Beta HydroxysteroidDehydrogenase Type I Inhibitors”, having the same assignee as thepresent invention and filed concomitantly herewith.

The present invention provides for compounds of formula I,pharmaceutical compositions employing such compounds, and for methods ofusing such compounds. In particular, the present invention provides apharmaceutical composition comprising a therapeutically effective amountof a compound of formula I, alone or in combination with apharmaceutically acceptable carrier.

Further, in accordance with the present invention, a method is providedfor preventing, inhibiting, or treating the progression or onset ofdiseases or disorders associated with the activity of the enzyme11-beta-hydroxysteroid dehydrogenase type I, such as defined above andhereinafter, wherein a therapeutically effective amount of a compound offormula I is administered to a mammalian, i.e., human, patient in needof treatment.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore other agent(s).

Further, the present invention provides a method for preventing,inhibiting, or treating the diseases as defined above and hereinafter,wherein a therapeutically effective amount of a combination of acompound of formula I and another compound of formula I and/or at leastone other type of therapeutic agent, is administered to a mammalian,i.e., human, patient in need of treatment.

DESCRIPTION OF THE INVENTION

In accordance with the present invention, compounds of formula I areprovidedW-L-Z  (I)enantiomers, diastereomers, solvates, salts or prodrugs thereof wherein:

-   -   W is aryl, cycloalkyl, heteroaryl or heterocyclyl, all of which        may be optionally substituted with R₁, R_(1a), R_(1b), R_(1c)        and R_(1d);    -   R₁, R_(1a), R_(1b), R_(1c) and R_(1d) are independently        hydrogen, halogen, —OH, —CN, —NO₂, —CO₂R_(2a), —CONR₂R_(2a),        —SO₂NR₂R_(2a), —SOR_(2a), —SO₂R_(2a), —NR₂SO₂R₆, —NR₂CO₂R₆,        alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, alkenyl,        haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino,        aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or        heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may        be optionally substituted with R₇, R_(7a), R_(7b), and R_(7c);    -   or alternatively any two R₁, R_(1a), R_(1b), R_(1c) and R_(1d)        can be taken together to form a fused aryl, heteroaryl,        heterocyclyl ring or spiro heterocyclyl ring;    -   L is a bond, O, S, SO, SO₂, alkenyl, cycloalkyl, NR₅, CR₂R_(2a),        CR₂R_(2a)CR_(2b)R_(2c), SO₂NR₂, OCR₂R_(2a),        OCR₂R_(2a)CR_(2b)R_(2c), CR₂R_(2a)O, CR_(2b)R_(2c)CR₂R_(2a)O,        N(R₅)CR₂R_(2a), CR₂R_(2a)N(R₅), SCR₂R_(2a), CR₂R_(2a)S,        CR₂R_(2a)SO, CR₂R_(2a)SO₂, SOCR₂R_(2a), SO₂CR₂R_(2a),        CR₂R_(2a)OCR_(2b)R_(2c), CR₂R_(2a)SCR_(2b)R_(2c),        CR₂R_(2a)SO₂CR_(2b)R_(2c), SO₂NR₂CR_(2a)R_(2b, COCR) ₂R_(2a),        CR₂R_(2a)CO, CONR₅CR_(2a)R_(2b), CR₂R_(2a)CR_(2b)R_(2c)S,        CR₂R_(2a)CR_(2b)R_(2c)SO, CR₂R_(2a)CR_(2b)R_(2c)SO₂, provided        that L is not a bond when W is phenyl;    -   R₂, R_(2a), R_(2b) and R_(2c) are independently hydrogen,        halogen, alkyl or haloalkyl;    -   or alternatively any two R₂, R_(2a), R_(2b), and R_(2c) can be        taken together to which the atom they are attached to form a        cycloalkyl, halogen substituted cycloalkyl or heterocyclyl ring;    -   Z is selected from the following bicyclic heteroaryl groups:

-   -   R₃, R_(3a) and R_(3b) are independently hydrogen, halogen, —OH,        —CN, —NO₂, —CO₂R_(2a), —CONR₂R_(2a), —SO₂NR₂R_(2a), —SOR_(2a),        —SO₂R_(2a), —NR₂SO₂R₆, —NR₂CO₂R₆, alkyl, haloalkyl, cycloalkyl,        alkoxy, aryloxy, alkenyl, haloalkoxy, alkylthio, arylthio,        arylsulfonyl, alkylamino, aminoalkyl, arylamino,        heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the        aryl, heteroaryl or heterocyclyl may be optionally substituted        with R₇, R_(7a), R_(7b), and R_(7c);    -   R₄ is bicyclo[2,2,2]octyl or bicyclo[2,2,1]heptyl, both of which        may be optionally substituted with one or more substituents        selected from halogen, —OH, —OR₆, —SR₆, —OCOR₆, —CN, —NR₅COR₆,        —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H, —OCONR₂R_(2a), —CONR₂R_(2a),        —NR₅CO₂R₆, —SO₂R₆, alkyl, alkoxy, aryl, amino, heterocyclyl or        heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or        heterocyclyl may be optionally substituted with R₇, R_(7a),        R_(7b), and R_(7c); or    -   R₄ is cycloalkyl, other than bicyclo[2,2,2]octyl or        bicyclo[2,2,1]heptyl, which may be optionally substituted with        one or more substituents selected from halogen, —OH, —OR₆, —SR₆,        —OCOR₆, —CN, —NR₅COR₆, —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H,        —OCONR₂R_(2a), —CONR₂R_(2a), —NR₅CO₂R₆, —SO₂R₆, alkyl, alkoxy,        aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl,        alkoxy, aryl, heteroaryl or heterocyclyl may be optionally        substituted with R₇, R_(7a), R_(7b), and R_(7c); or    -   R₄ is heterocyclyl, which may be optionally substituted with one        or more substituents selected from halogen, —OH, —OR₆, —SR₆,        —OCOR₆, —CN, —NR₅COR₆, —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H,        —OCONR₂R_(2a), —CONR₂R_(2a), —NR₅CO₂R₆, —SO₂R₆, alkyl, alkoxy,        aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl,        alkoxy, aryl, heteroaryl or heterocyclyl may be optionally        substituted with R₇, R_(7a), R_(7b), and R_(7c); or    -   R₄ is alkyl, which may be optionally substituted with one or        more substituents selected from halogen, —OH, —OR₆, —SR₆,        —OCOR₆, —CN, —NR₅COR₆, —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H,        —OCONR₂R_(2a), —CONR₂R_(2a), —NR₅CO₂R₆, —SO₂R₆, alkyl, alkoxy,        aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl,        alkoxy, aryl, heteroaryl or heterocyclyl may be optionally        substituted with R₇, R_(7a), R_(7b), and R_(7c);    -   R_(4a) is hydrogen, CN, alkyl, haloalkyl, aryl, substituted        aryl, heteroaryl or substituted heteroaryl;    -   R₅, at each occurrence, is independently hydrogen, alkyl,        cycloalkyl, aryl, haloalkyl, COR_(2a), CO₂R_(2a), SO₂NR₂R_(2a),        or SO₂R_(2a);    -   R₆, at each occurrence, is independently alkyl, cycloalkyl, aryl        or heteroaryl, all of which may be optionally substituted with        R₇, R_(7a), R_(7b), and R_(7c); and    -   R₇, R_(7a), R_(7b), and R_(7c), at each occurrence, are        independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy,        arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl,        cycloalkylalkyl, cycloalkylalkyloxy, amino, —OH, hydroxyalkyl,        acyl, heteroaryl, heteroaryloxy, heteroarylalkyl,        heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio,        aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —NO₂,        —CN or thiol.

In another embodiment, compounds of formula I are those in which W isaryl, which is optionally substituted with R₁, R_(1a), R_(1b), R_(1c)and R_(1d).

In another embodiment, compounds of formula I are those in which W isphenyl, which is optionally substituted with R₁, R_(1a), R_(1b), R_(1c)and R_(1d).

In another embodiment, compounds of formula I are those in which Z isselected from the following bicyclic heteroaryl groups:

In another embodiment, compounds of formula I are those in which Z isselected from the following bicyclic heteroaryl groups:

In yet another embodiment, compounds of formula I are those in which Lis O.

In another embodiment, compounds of formula I are those in which:

-   -   R₄ is bicyclo[2,2,2]octyl or bicyclo[2,2,1]heptyl, both of which        may be optionally substituted with one or more substituents        selected from halogen, —OH, —OR₆, —SR₆, —OCOR₆, —CN, —NR₅COR₆,        —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H, —OCONR₂R_(2a), —CONR₂R_(2a),        —NR₅CO₂R₆, —SO₂R₆, alkyl, alkoxy, aryl, amino, heterocyclyl or        heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or        heterocyclyl may be optionally substituted with R₇, R_(7a),        R_(7b), and R_(7c); or    -   R₄ is cycloalkyl, other than bicyclo[2,2,2]octyl or        bicyclo[2,2,1 ]heptyl, which may be optionally substituted with        one or more substituents selected from halogen, —OH, —OR₆, —SR₆,        —OCOR₆, —CN, —NR₅COR₆, —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H,        —OCONR₂R_(2a), —CONR₂R_(2a), —NR₅CO₂R₆, —SO₂R₆, alkyl, alkoxy,        aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl,        alkoxy, aryl, heteroaryl or heterocyclyl may be optionally        substituted with R₇, R_(7a), R_(7b), and R_(7c); or    -   R₄ is heterocyclyl, which may be optionally substituted with one        or more substituents selected from halogen, —OH, —OR₆, —SR₆,        —OCOR₆, —CN, —NR₅COR₆, —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H,        —OCONR₂R_(2a), —CONR₂R_(2a), —NR₅CO₂R₆, —SO₂R₆, alkyl, alkoxy,        aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl,        alkoxy, aryl, heteroaryl or heterocyclyl may be optionally        substituted with R₇, R_(7a), R_(7b), and R_(7c);    -   R₅, at each occurrence, is independently hydrogen, alkyl,        cycloalkyl, aryl, haloalkyl, COR_(2a), CO₂R_(2a), SO₂NR₂R_(2a),        or SO₂R_(2a);    -   R_(6,) at each occurrence, is independently alkyl, cycloalkyl,        aryl or heteroaryl, all of which may be optionally substituted        with R₇, R_(7a), R_(7b), and R_(7c); and    -   R₇, R_(7a), R_(7b), and R_(7c), at each occurrence, are        independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy,        arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl,        cycloalkylalkyl, cycloalkylalkyloxy, amino, —OH, hydroxyalkyl,        acyl, heteroaryl, heteroaryloxy, heteroarylalkyl,        heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio,        aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —NO₂,        —CN or thiol.

In still yet another embodiment, compounds of formula I are those inwhich:

-   -   Z is selected from the following bicyclic heteroaryl groups:

-   -   R₄ is bicyclo[2,2,2]octyl or bicyclo[2,2,1]heptyl, both of which        may be optionally substituted with one or more substituents        selected from halogen, —OH, —OR₆, —SR₆, —OCOR₆, —CN, —NR₅COR₆,        —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H, —OCONR₂R_(2a), —CONR₂R_(2a),        —NR₅CO₂R₆, —SO₂R₆, alkyl, alkoxy, aryl, amino, heterocyclyl or        heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or        heterocyclyl may be optionally substituted with R₇, R_(7a),        R_(7b), and R_(7c); or    -   R₄ is cycloalkyl, other than bicyclo[2,2,2]octyl or        bicyclo[2,2,1]heptyl, which may be optionally substituted with        one or more substituents selected from halogen, —OH, —OR₆, —SR₆,        —OCOR₆, —CN, —NR₅COR₆, —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H,        —OCONR₂R_(2a), —CONR₂R_(2a), —NR₅CO₂R₆, —SO₂R₆, alkyl, alkoxy,        aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl,        alkoxy, aryl, heteroaryl or heterocyclyl may be optionally        substituted with R₇, R_(7a), R_(7b), and R_(7c);    -   R₅, at each occurrence, is independently hydrogen, alkyl,        cycloalkyl, aryl, haloalkyl, COR_(2a), CO₂R_(2a), SO₂NR₂R_(2a),        or SO₂R_(2a);    -   R₆, at each occurrence, is independently alkyl, cycloalkyl, aryl        or heteroaryl, all of which may be optionally substituted with        R₇, R_(7a), R_(7b), and R_(7c); and    -   R₇, R_(7a), R_(7b), and R_(7c), at each occurrence, are        independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy,        arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl,        cycloalkylalkyl, cycloalkylalkyloxy, amino, —OH, hydroxyalkyl,        acyl, heteroaryl, heteroaryloxy, heteroarylalkyl,        heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio,        aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —NO₂,        —CN or thiol.

In one embodiment, compounds of formula I are those in which:

-   -   W is aryl, cycloalkyl or heteroaryl, all of which may be        optionally substituted with R₁, R_(1a), R_(1b), R_(1c) and        R_(1d);    -   R₁, R_(1a), R_(1b), R_(1c) and R_(1d) are independently        hydrogen, halogen, —OH, —CN, —NO₂, —CO₂R_(2a), —CONR₂R_(2a),        —SO₂NR₂R_(2a), —SOR_(2a), —SO₂R_(2a), —NR₂SO₂R₆, —NR₂CO₂R₆,        alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, alkenyl,        haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino,        aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or        heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may        be optionally substituted with R₇, R_(7a), R_(7b), and R_(7c);    -   L is a bond, O, S, SO₂, CR₂R_(2a), SO₂NR₂, OCR₂R_(2a),        OCR₂R_(2a)CR_(2b)R_(2c), CR₂R_(2a)O, CR_(2b)R_(2c)CR₂R_(2a)O,        SCR₂R_(2a), CR₂R_(2a)S, CR₂R_(2a)SO, CR₂R_(2a)SO₂, SO₂CR₂R_(2a),        CR₂R_(2a)OCR_(2b)R_(2c), CR₂R_(2a)SCR_(2b)R_(2c),        CR₂R_(2a)SO₂CR_(2b)R_(2c), SO₂NR₂CR_(2a)R_(2b), COCR₂R_(2a),        CR₂R_(2a)CO, CONR₅CR_(2a)R_(2b), CR₂R_(2a)CR_(2b)R_(2c)S,        CR₂R_(2a)CR_(2b)R_(2c)SO, or CR₂R_(2a)CR_(2b)R_(2c)SO₂;    -   R₂, R_(2a), R_(2b) and R_(2c) are independently hydrogen,        halogen, alkyl or haloalkyl;    -   Z is selected from the following bicyclic heteroaryl groups:

-   -   R₃, R_(3a) and R_(3b) are independently hydrogen, halogen, —OH,        —CN, —NO₂, —CO₂R_(2a), —CONR₂R_(2a), —SO₂NR₂R_(2a), —SOR_(2a),        —SO₂R_(2a), —NR₂SO₂R₆, —NR₂CO₂R₆, alkyl, haloalkyl, cycloalkyl,        alkoxy, aryloxy, alkenyl, haloalkoxy, alkylthio, arylthio,        arylsulfonyl, alkylamino, aminoalkyl, arylamino,        heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the        aryl, heteroaryl or heterocyclyl may be optionally substituted        with R₇, R_(7a), R_(7b), and R_(7c);    -   R₄ is bicyclo[2,2,2]octyl or bicyclo[2,2,1]heptyl, both of which        may be optionally substituted with one or more substituents        selected from halogen, —OH, —OR₆, —SR₆, —OCOR₆, —CN, —NR₅COR₆,        —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H, —OCONR₂R_(2a), —CONR₂R_(2a),        —NR₅CO₂R₆, —SO₂R₆, alkyl, alkoxy, aryl, amino, heterocyclyl or        heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or        heterocyclyl may be optionally substituted with R₇, R_(7a),        R_(7b), and R_(7c); or    -   R₄ is cycloalkyl, other than bicyclo[2,2,2]octyl or        bicyclo[2,2,1]heptyl, which may be optionally substituted with        one or more substituents selected from halogen, —OH, —OR₆, —SR₆,        —OCOR₆, —CN, —NR₅COR₆, —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H,        —OCONR₂R_(2a), —CONR₂R_(2a), —NR₅CO₂R₆, —SO₂R₆, alkyl, alkoxy,        aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl,        alkoxy, aryl, heteroaryl or heterocyclyl may be optionally        substituted with R₇, R_(7a), R_(7b), and R_(7c); or    -   R₄ is heterocyclyl, which may be optionally substituted with one        or more substituents selected from halogen, —OH, —OR₆, —SR₆,        —OCOR₆, —CN, —NR₅COR₆, —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H,        —OCONR₂R_(2a), —CONR₂R_(2a), —NR₅CO₂R₆, —SO₂R₆, alkyl, alkoxy,        aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl,        alkoxy, aryl, heteroaryl or heterocyclyl may be optionally        substituted with R₇, R_(7a), R_(7b), and R_(7c);    -   R_(4a) is hydrogen, alkyl, or haloalkyl;    -   R₅, at each occurrence, is independently hydrogen, alkyl,        cycloalkyl, aryl, haloalkyl, COR_(2a)or CO₂R_(2a);    -   R₆, at each occurrence, is independently alkyl, cycloalkyl, aryl        or heteroaryl, all of which may be optionally substituted with        R₇, R_(7a), R_(7b), and R_(7c); and    -   R₇, R_(7a), R_(7b), and R_(7c), at each occurrence, are        independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy,        arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl,        cycloalkylalkyl, cycloalkylalkyloxy, amino, —OH, hydroxyalkyl,        acyl, heteroaryl, heteroaryloxy, heteroarylalkyl,        heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio,        aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —NO₂,        —CN or thiol.

In another embodiment, compounds of formula I are those in which:

-   -   W is aryl, cycloalkyl or heteroaryl, all of which may be        optionally substituted with R₁, R_(1a), R_(1b), R_(1c) and        R_(1d);    -   R₁, R_(1a), R_(1b), R_(1c) and R_(1d) are independently        hydrogen, halogen, —OH, —CN, —NO₂, —CO₂R_(2a), —CONR₂R_(2a),        —SO₂NR₂R_(2a), —SOR_(2a), —SO₂R_(2a), alkyl, haloalkyl,        cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio,        arylsulfonyl, alkylamino, aminoalkyl, arylamino,        heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the        aryl, heteroaryl or heterocyclyl may be optionally substituted        with R₇, R_(7a), R_(7b), and R_(7c);    -   L is a bond, O, S, SO, SO₂, NR₂, CR₂R_(2a),        CR₂R_(2a)CR_(2b)R_(2c), OCR₂R_(2a), CR₂R_(2a)O, SCR₂R_(2a),        CR₂R_(2a)S, CR₂R_(2a)OCR_(2b)R_(2c), CR₂R_(2a)SCR_(2b)R_(2c),        CR₂R_(2a)SO₂CR_(2b)R_(2c) or SO₂NR₂CR_(2a)R_(2b);    -   R₂, R_(2a), R_(2b) and R_(2c) are independently hydrogen,        halogen, alkyl or haloalkyl;    -   Z is selected from the following bicyclic heteroaryl groups:

-   -   R₃, R_(3a) and R_(3b) are independently hydrogen, halogen, —OH,        —CN, —NO₂, —CO₂R_(2a), —CONR₂R_(2a), —SO₂NR₂R_(2a), —SOR_(2a),        —SO₂R_(2a), alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy,        haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino,        aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or        heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may        be optionally substituted with R₇, R_(7a), R_(7b), and R_(7c);    -   R₄ is bicyclo[2,2,2]octyl or bicyclo[2,2,1]heptyl, both of which        may be optionally substituted with one or more substituents        selected from halogen, —OH, —OR₆, —SR₆, —OCOR₆, —CN, —COR₆,        —CO₂R₆, —CO₂H, —OCONR₂R_(2a), —CONR₂R_(2a), —SO₂R₆, alkyl,        alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the        alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be        optionally substituted with R₇, R_(7a), R_(7b), and R_(7c); or    -   R₄ is cycloalkyl, other than bicyclo[2,2,2]octyl or        bicyclo[2,2,1]heptyl, which may be optionally substituted with        one or more substituents selected from halogen, —OH, —OR₆, —SR₆,        —OCOR₆, —CN, —COR₆, —CO₂R₆, —CO₂H, —OCONR₂R_(2a), —CONR₂R_(2a),        —SO₂R₆, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl,        wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may        be optionally substituted with R₇, R_(7a), R_(7b), and R_(7c);        or    -   R₄ is heterocyclyl, which may be optionally substituted with one        or more substituents selected from halogen, —OH, —OR₆, —SR₆,        —OCOR₆, —CN, —COR₆, —CO₂R₆, —CO₂H, —OCONR₂R_(2a), —CONR₂R_(2a),        —SO₂R₆, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl,        wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may        be optionally substituted with R₇, R_(7a), R_(7b), and R_(7c);    -   R₆, at each occurrence, is independently alkyl, cycloalkyl, aryl        or heteroaryl, all of which may be optionally substituted with        R₇, R_(7a), R_(7b), and R_(7c); and    -   R₇, R_(7a), R_(7b), and R_(7c), at each occurrence, are        independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy,        arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl,        cycloalkylalkyl, cycloalkylalkyloxy, amino, —OH, hydroxyalkyl,        acyl, heteroaryl, heteroaryloxy, heteroarylalkyl,        heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio,        aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —NO₂,        —CN or thiol.

In yet another embodiment, compounds of formula I are those in which:

-   -   W is aryl or heteroaryl, both of which may be optionally        substituted with R₁, R_(1a), R_(1b), R_(1c) and R_(1d);    -   R₁, R_(1a), R_(1b), R_(1c) and R_(1d) are independently        hydrogen, halogen, —OH, —CN, —NO₂, —CO₂R_(2a), —CONR₂R_(2a),        —SO₂NR₂R_(2a), alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy,        haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino,        aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or        heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may        be optionally substituted with R₇, R_(7a), R_(7b), and R_(7c);    -   L is a bond, O, S, SO, SO₂, CR₂R_(2a), OCR₂R_(2a), CR₂R_(2a)O,        SO₂NR₂CR_(2a)R_(2b) or CR₂R_(2a)OCR_(2b)R_(2c);    -   R₂, R_(2a), R_(2b) and R_(2c) are independently hydrogen,        halogen, alkyl or haloalkyl;    -   Z is selected from the following bicyclic heteroaryl groups:

-   -   R₃, R_(3a) and R_(3b) are independently hydrogen, halogen, —OH,        —CN, —NO₂, —CO₂R_(2a), —CONR₂R_(2a), —SO₂NR₂R_(2a), alkyl,        haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio,        arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino,        heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the        aryl, heteroaryl or heterocyclyl may be optionally substituted        with R₇, R_(7a), R_(7b), and R_(7c);    -   R₄ is bicyclo[2,2,2]octyl or bicyclo[2,2,1]heptyl, both of which        may be optionally substituted with one or more substituents        selected from halogen, —OH, —OR₆, —SR₆, —OCOR₆, —CN, —COR₆,        —CO₂R₆, —CO₂H, —OCONR₂R_(2a), —CONR₂R_(2a), —SO₂R₆, alkyl,        alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the        alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may be        optionally substituted with R₇, R_(7a), R_(7b), and R_(7c); or    -   R₄ is cycloalkyl, other than bicyclo[2,2,2]octyl or        bicyclo[2,2,1]heptyl, which may be optionally substituted with        one or more substituents selected from halogen, —OH, —OR₆, —SR,        —OCOR₆, —CN, —COR₆, —CO₂R₆, —CO₂H, —OCONR₂R_(2a),        —CONR₂R_(2a)—SO₂R₆, alkyl, alkoxy, aryl, amino, heterocyclyl or        heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or        heterocyclyl may be optionally substituted with R₇, R_(7a),        R_(7b), and R_(7c); or    -   R₄ is heterocyclyl, which may be optionally substituted with one        or more substituents selected from halogen, —OH, —OR₆, —SR₆,        —OCOR₆, —CN, —COR₆, —CO₂R₆, —CO₂H, —OCONR₂R_(2a), —CONR₂R_(2a),        —SO₂R₆, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl,        wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may        be optionally substituted with R₇, R_(7a), R_(7b), and R_(7c);    -   R₆, at each occurrence, is independently alkyl, cycloalkyl, aryl        or heteroaryl, all of which may be optionally substituted with        R₇, R_(7a), R_(7b), and R_(7c); and    -   R₇, R_(7a), R_(7b), and R_(7c), at each occurrence, are        independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy,        arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl,        cycloalkylalkyl, cycloalkylalkyloxy, amino, —OH, hydroxyalkyl,        acyl, heteroaryl, heteroaryloxy, heteroarylalkyl,        heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio,        aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —NO₂,        —CN or thiol.

In still yet another embodiment, the compounds of formula I are those inwhich:

-   -   W is aryl or heteroaryl, both of which may be optionally        substituted with R₁, R_(1a), R_(1b), R_(1c) and R_(1d);    -   R₁, R_(1a), R_(1b), R_(1c) and R_(1d) are independently        hydrogen, halogen, —OH, —CN, —NO₂, —CO₂R_(2a), alkyl, haloalkyl,        cycloalkyl, alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio,        arylsulfonyl, alkylamino, aminoalkyl, arylamino,        heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the        aryl, heteroaryl or heterocyclyl may be optionally substituted        with R₇, R_(7a), R_(7b), and R_(7c);    -   L is a bond, O, S, SO, SO₂, CR₂R_(2a), OCR₂R_(2a), CR₂R_(2a)O,        SO₂NR₂CR_(2a)R_(2b) or CR₂R_(2a)OCR_(2b)R_(2c);    -   R₂, R_(2a), R_(2b) and R_(2c) are independently hydrogen,        halogen, alkyl or haloalkyl;    -   Z is selected from the following bicyclic heteroaryl groups:

-   -   R₃, R_(3a) and R_(3b) are independently hydrogen, halogen, —OH,        —CN, —NO₂, —CO₂R_(2a), alkyl, haloalkyl, cycloalkyl, alkoxy,        aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl,        alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl,        heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or        heterocyclyl may be optionally substituted with R₇, R_(7a),        R_(7b), and R_(7c);    -   R₄ is bicyclo[2,2,2]octyl or bicyclo[2,2,1]heptyl, both of which        may be optionally substituted with one or more substituents        selected from halogen, —OH, —OR₆, —SR₆, —CN, —COR₆, —CO₂R₆,        —CO₂H, —CONR₂R_(2a), —SO₂R₆, alkyl, alkoxy, aryl, amino,        heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl,        heteroaryl or heterocyclyl may be optionally substituted with        R₇, R_(7a), R_(7b), and R_(7c); or    -   R₄ is cycloalkyl, other than bicyclo[2,2,2]octyl or        bicyclo[2,2,1]heptyl, which may be optionally substituted with        one or more substituents selected from halogen, —OH, —OR₆, —SR₆,        —CN, —CO₆, —CO₂R₆, —CO₂H, —CONR₂R_(2a), —SO₂R₆, alkyl, alkoxy,        aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl,        alkoxy, aryl, heteroaryl or heterocyclyl may be optionally        substituted with R₇, R_(7a), R_(7b), and R_(7c); or    -   R₄ is heterocyclyl, which may be optionally substituted with one        or more substituents selected from halogen, —OH, —OR₆, —SR₆,        —CN, —COR₆, —CO₂R₆, —CO₂H, —CONR₂R_(2a), —SO₂R₆, alkyl, alkoxy,        aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl,        alkoxy, aryl, heteroaryl or heterocyclyl may be optionally        substituted with R₇, R_(7a), R_(7b), and R_(7c);    -   R₆, at each occurrence, is independently alkyl, cycloalkyl, aryl        or heteroaryl, all of which may be optionally substituted with        R₇, R_(7a), R_(7b), and R_(7c); and    -   R₇, R_(7a), R_(7b), and R_(7c), at each occurrence, are        independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy,        arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl,        cycloalkylalkyl, cycloalkylalkyloxy, amino, —OH, hydroxyalkyl,        acyl, heteroaryl, heteroaryloxy, heteroarylalkyl,        heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio,        aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —NO₂,        —CN or thiol.

In one embodiment, compounds of formula I are those in which:

-   -   W is aryl, which is optionally substituted with R₁, R_(1a),        R_(1b), R_(1c) and R_(1d);    -   R₁, R_(1a), R_(1b), R_(1c) and R_(1d) are independently        hydrogen, halogen, —OH, —CN, —NO₂, alkyl, haloalkyl, cycloalkyl,        alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl,        alkylamino, aminoalkyl, arylamino, heteroarylamino, aryl,        heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or        heterocyclyl may be optionally substituted with R₇, R_(7a),        R_(7b), and R_(7c);    -   L is a bond, O, S, SO, SO₂, CR₂R_(2a), OCR₂R_(2a), CR₂R_(2a)O,        SO₂NR₂CR_(2a)R_(2b) or CR₂R_(2a)OCR_(2b)R_(2c);    -   R₂, R_(2a), R_(2b) and R_(2c) are independently hydrogen,        halogen, alkyl or haloalkyl;    -   Z is selected from the following bicyclic heteroaryl groups:

-   -   R₃, R_(3a) and R_(3b) are independently hydrogen, halogen, —OH,        —CN, —NO₂, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy,        haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino,        aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl or        heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may        be optionally substituted with R₇, R_(7a), R_(7b), and R_(7c);    -   R₄ is bicyclo[2,2,2]octyl or bicyclo[2,2,1]heptyl, both of which        may be optionally substituted with one or more substituents        selected from halogen, —OH, —OR₆, —SR₆, —CN, —COR₆, —CO₂R₆,        —CO₂H, CONR₂R_(2a), SO₂R₆, alkyl, alkoxy, aryl, amino,        heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl,        heteroaryl or heterocyclyl may be optionally substituted with        R₇, R_(7a), R_(7b), and R_(7c); or    -   R₄ is cycloalkyl, other than bicyclo[2,2,2]octyl or        bicyclo[2,2,1]heptyl, which may be optionally substituted with        one or more substituents selected from halogen, —OH, —OR₆, —SR₆,        —CN, —COR₆, —CO₂R₆, —CO₂H, —CONR₂R_(2a), —SO₂R₆, alkyl, alkoxy,        aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl,        alkoxy, aryl, heteroaryl or heterocyclyl may be optionally        substituted with R₇, R_(7a), R_(7b), and R_(7c);    -   R₆, at each occurrence, is independently alkyl, cycloalkyl, aryl        or heteroaryl, all of which may be optionally substituted with        R₇, R_(7a), R_(7b), and R_(7c); and    -   R₇, R_(7a), R_(7b), and R_(7c), at each occurrence, are        independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy,        arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl,        cycloalkylalkyl, cycloalkylalkyloxy, amino, —OH, hydroxyalkyl,        acyl, heteroaryl, heteroaryloxy, heteroarylalkyl,        heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio,        aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —NO₂,        —CN or thiol.

In another embodiment, compounds of formula I are those in which:

-   -   W is aryl, which is optionally substituted with R₁, R_(1a),        R_(1b), R_(1c) and R_(1d);    -   R₁, R_(1a), R_(1b), R_(1c) and R_(1d) are hydrogen, halogen,        —OH, —CN, —NO₂, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy,        haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino,        aminoalkyl, aryl, heteroaryl or heterocyclyl, wherein the aryl,        heteroaryl or heterocyclyl may be optionally substituted with        R₇, R_(7a), R_(7b), and R_(7c);    -   L is a bond, O, S, CR₂R_(2a), OCR₂R_(2a), CR₂R_(2a)O or        CR₂R_(2a)OCR_(2b)R_(2c);    -   R₂, R_(2a), R_(2b) and R_(2c) are independently hydrogen,        halogen, alkyl or haloalkyl;    -   Z is selected from the following bicyclic heteroaryl groups:

R₃, R_(3a) and R_(3b) are independently hydrogen, halogen, —OH, —CN,—NO₂, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy, haloalkoxy,alkylthio, arylthio, arylsulfonyl, alkylamino, aminoalkyl, aryl,heteroaryl or heterocyclyl, wherein the aryl, heteroaryl or heterocyclylmay be optionally substituted with R₇, R_(7a), R_(7b), and R_(7c);

-   -   R₄ is bicyclo[2,2,2]octyl or bicyclo[2,2,1]heptyl, both of which        may be optionally substituted with one or more substituents        selected from halogen, —OH, —OR₆, —SR₆, —CN, —COR₆, —CO₂R₆,        —CO₂H, alkyl, alkoxy, aryl, amino, heterocyclyl or heteroaryl,        wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclyl may        be optionally substituted with R₇, R_(7a), R_(7b), and R_(7c);        or    -   R₄ is cycloalkyl, other than bicyclo[2,2,2]octyl or        bicyclo[2,2,1]heptyl, which may be optionally substituted with        one or more substituents selected from halogen, —OH, —OR₆, —SR₆,        —CN, —COR₆, —CO₂R₆, —CO₂H, alkyl, alkoxy, aryl, amino,        heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl,        heteroaryl or heterocyclyl may be optionally substituted with        R₇, R_(7a), R_(7b), and R_(7c);    -   R₆ at each occurrence, is independently alkyl, cycloalkyl, aryl        or heteroaryl; and    -   R₇, R_(7a), R_(7b), and R_(7c), at each occurrence, are        independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy,        arylaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl,        cycloalkylalkyl, cycloalkylalkyloxy, amino, —OH, hydroxyalkyl,        acyl, heteroaryl, heteroaryloxy, heteroarylalkyl,        heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio,        aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, —NO₂,        —CN or thiol.

In another embodiment, compounds of formula I are those in which:

-   -   W is phenyl, which is optionally substituted with R₁, R_(1a),        R_(1b), R_(1c) and R_(1d);    -   R₁, R_(1a), R_(1b), R_(1c) and R_(1d) are independently        hydrogen, halogen, —OH, —CN, —NO₂, alkyl, haloalkyl, cycloalkyl,        alkoxy, aryloxy, haloalkoxy, alkylthio, arylthio, arylsulfonyl,        alkylamino, aminoalkyl, aryl, heteroaryl or heterocyclyl;    -   L is O, S, SCH₂, OCH₂, CH₂O or CH₂OCH₂;    -   Z is selected from the following bicyclic heteroaryl groups:

-   -   R₃, R_(3a) and R_(3b) are independently hydrogen, halogen, —OH,        —CN, —NO₂, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy,        haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino,        aminoalkyl, aryl, heteroaryl or heterocyclyl;    -   R₄ is bicyclo[2,2,2]octyl or bicyclo[2,2,1]heptyl, all which may        be optionally substituted with one or more substituents selected        from halogen, —OH, —OR₆, —SR₆, —CN, alkyl, alkoxy, aryl, amino,        heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl,        heteroaryl or heterocyclyl may be optionally substituted with        R₇, R_(7a), R_(7b), and R_(7c);    -   R₆, at each occurrence, is independently alkyl, cycloalkyl, aryl        or heteroaryl; and    -   R₇, R_(7a), R_(7b), and R_(7c), at each occurrence, are        independently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy,        arylalkyl, cycloalkyl, amino, —OH, hydroxyalkyl, heteroaryl,        heteroaryloxy, heteroarylalkyl, alkylthio, arylalkylthio, —NO₂,        or —CN.

In another embodiment, compounds of the present invention are selectedfrom the compounds exemplified in the examples.

In another embodiment, the present invention relates to pharmaceuticalcompositions comprised of a therapeutically effective amount of acompound of the present invention, alone or, optionally, in combinationwith a pharmaceutically acceptable carrier and/or one or more otheragent(s).

In another embodiment, the present invention relates to methods ofinhibiting the activity of the enzyme 11-beta-hydroxysteroiddehydrogenase type I comprising administering to a mammalian patient,for example, a human patient, in need thereof a therapeuticallyeffective amount of a compound of the present invention, alone, oroptionally, in combination with another compound of the presentinvention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset of diseasesor disorders associated with the activity of the enzyme11-beta-hydroxysteroid dehydrogenase type I comprising administering toa mammalian patient, for example, a human patient, in need ofprevention, inhibition, or treatment a therapeutically effective amountof a compound of the present invention, alone, or, optionally, incombination with another compound of the present invention and/or atleast one other type of therapeutic agent.

Examples of diseases or disorders associated with the activity of theenzyme 11-beta-hydroxysteroid dehydrogenase type I that can beprevented, inhibited, or treated according to the present inventioninclude, but are not limited to, diabetes, hyperglycemia, impairedglucose tolerance, insulin resistance, hyperinsulinemia, retinopathy,neuropathy, nephropathy, delayed wound healing, atherosclerosis, acutecoronary syndrome, myocardial infarction, angina pectoris, peripheralvascular disease, intermitant claudication, abnormal heart function,myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity,dislipidemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low HDL, high LDL, non-cardiac ischemia,infection, cancer, vascular restenosis, pancreatitis, neurodegenerativedisease, lipid disorders, cognitive impairment and dementia, bonedisease, HIV protease associated lipodystrophy, glaucoma, rheumatoidarthritis and osteoarthritis.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofdiabetes, hyperglycemia, obesity, dislipidemia, hypertension, cognitiveimpairment, rheumatoid arthritis, osteoarthritis, glaucoma and MetabolicSyndrome comprising administering to a mammalian patient, for example, ahuman patient, in need of prevention, inhibition, or treatment atherapeutically effective amount of a compound of the present invention,alone, or, optionally, in combination with another compound of thepresent invention and/or at least one other type of therapeutic agent.

In still another embodiment, the present invention relates to a methodfor preventing, inhibiting, or treating the progression or onset ofdiabetes, comprising administering to a mammalian patient, for example,a human patient, in need of prevention, inhibition, or treatment atherapeutically effective amount of a compound of the present invention,alone, or, optionally, in combination with another compound of thepresent invention and/or at least one other type of therapeutic agent.

In yet still another embodiment, the present invention relates to amethod for preventing;. inhibiting, or treating the progression or onsetof hyperglycemia comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a compound of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset of obesitycomprising administering to a mammalian patient, for example, a humanpatient, in need of prevention, inhibition, or treatment atherapeutically effective amount of a compound of the present invention,alone, or, optionally, in combination with another compound of thepresent invention and/or at least one other type of therapeutic agent.

In one embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofdislipidemia comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a compound of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofhypertension comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a compound of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofcognitive impairment comprising administering to a mammalian patient,for example, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a compound of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofrheumatoid arthritis comprising administering to a mammalian patient,for example, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a compound of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofosteoarthritis comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a compound of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofMetabolic Syndrome comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a compound of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In still another embodiment, the present invention relates to a methodfor preventing, inhibiting, or treating the progression or onset ofglaucoma, comprising administering to a mammalian patient, for example,a human patient, in need of prevention, inhibition, or treatment atherapeutically effective amount of a compound of the present invention,alone, or, optionally, in combination with another compound of thepresent invention and/or at least one other type of therapeutic agent.

Definitions

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric racemic forms, and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom or ring is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalency is not exceeded, and that the substitution results in a stablecompound. When a substituent is keto (i.e., ═O), then 2 hydrogens on theatom are replaced.

When any variable (e.g., R^(a)) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R^(a), then saidgroup may optionally be substituted with up to two R^(a) groups andR^(a) at each occurrence is selected independently from the definitionof R^(a). Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

Unless otherwise indicated, the term “lower alkyl,” “alkyl,” or “alk” asemployed herein alone or as part of another group includes both straightand branched chain hydrocarbons, containing 1 to 20 carbons, preferably1 to 10 carbons, more preferably 1 to 8 carbons, in the normal chain,such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl,pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethyl-pentyl, nonyl, decyl, undecyl, dodecyl, the variousbranched chain isomers thereof, and the like as well as such groups mayoptionally include 1 to 4 substituents such as halo, for example F, Br,Cl, or I, or CF₃, alkyl, alkoxy, aryl, aryloxy, aryl(aryl) or diaryl,arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkyloxy, amino, hydroxy, hydroxyalkyl, acyl, heteroaryl,heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl,alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino,arylcarbonylamino, nitro, cyan, thiol, haloalkyl, trihaloalkyl, and/oralkylthio.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or as part of another group includes saturated or partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 3 rings, including monocyclic alkyl, bicyclic alkyl (orbicycloalkyl) and tricyclic alkyl, containing a total of 3 to 20 carbonsforming the ring, preferably 3 to 10 carbons, forming the ring and whichmay be fused to 1 or 2 aromatic rings as described for aryl, whichincludes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl,

any of which groups may be optionally substituted with 1 to 4substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy,arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl,arylcarbonylamino, amino, nitro, cyano, thiol, and/or alkylthio, and/orany of the substituents for alkyl.

Unless otherwise indicated, the term “lower alkenyl” or “alkenyl” asused herein by itself or as part of another group refers to straight orbranched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons,and more preferably 1 to 8 carbons in the normal chain, which includeone to six double bonds in the normal chain, such as vinyl, 2-propenyl,3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl,2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl,3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like, andwhich may be optionally substituted with 1 to 4 substituents, namely,halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl,cycloalkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino,alkylamido, arylcarbonyl-amino, nitro, cyano, thiol, alkylthio, and/orany of the alkyl substituents set out herein.

Unless otherwise indicated, the term “lower alkynyl” or “alkynyl” asused herein by itself or as part of another group refers to straight orbranched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbonsand more preferably 2 to 8 carbons in the normal chain, which includeone triple bond in the normal chain, such as 2-propynyl, 3-butynyl,2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl,3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl,3-undecynyl,4-dodecynyl, and the like, and which may be optionally substituted with1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl,alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl,cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido, arylcarbonylamino,nitro, cyano, thiol, and/or alkylthio, and/or any of the alkylsubstituents set out herein.

Where alkyl groups as defined above have single bonds for attachment toother groups at two different carbon atoms, they are termed “alkylene”groups and may optionally be substituted as defined above for “alkyl”.

Where alkenyl groups as defined above and alkynyl groups as definedabove, respectively, have single bonds for attachment at two differentcarbon atoms, they are termed “alkenylene groups” and “alkynylenegroups”, respectively, and may optionally be substituted as definedabove for “alkenyl” and “alkynyl”.

The term “halogen” or “halo” as used herein alone or as part of anothergroup refers to chlorine, bromine, fluorine, and iodine as well as CF₃,with chlorine or fluorine being preferred.

Unless otherwise indicated, the term “aryl” as employed herein alone oras part of another group refers to monocyclic and bicyclic aromaticgroups containing 6 to 10 carbons in the ring portion (such as phenyl ornaphthyl, including 1-naphthyl and 2-naphthyl) and may optionallyinclude 1 to 3 additional rings fused to a carbocyclic ring or aheterocyclic ring (such as aryl, cycloalkyl, heteroaryl, orcycloheteroalkyl rings for example

and may be optionally substituted through available carbon atoms with 1,2, or 3 substituents, for example, hydrogen, halo, haloalkyl, alkyl,haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl,trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl,cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy,aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl,heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro,cyano, amino, substituted amino wherein the amino includes 1 or 2substituents (which are alkyl, aryl, or any of the other aryl compoundsmentioned in the definitions), thiol, alkylthio, arylthio,heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl,arylcarbonyl, alkyl-aminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino,or arylsulfon-aminocarbonyl, and/or any of the alkyl substituents setout herein.

Unless otherwise indicated, the term “lower alkoxy”, “alkoxy”, “aryloxy”or “aralkoxy” as employed herein alone or as part of another groupincludes any of the above alkyl, aralkyl, or aryl groups linked to anoxygen atom.

Unless otherwise indicated, the term “amino” as employed herein alone oras part of another group refers to amino that may be substituted withone or two substituents, which may be the same or different, such asalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl,cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, or thioalkyl. These substituents may befurther substituted with a carboxylic acid and/or any of the R¹ groupsor substituents for R¹ as set out above. In addition, the aminosubstituents may be taken together with the nitrogen atom to which theyare attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl,4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl,4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl,1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy,alkylthio, halo, trifluoromethyl, or hydroxy.

Unless otherwise indicated, the term “lower alkylthio,” “alkylthio,”“arylthio,” or “aralkylthio” as employed herein alone or as part ofanother group includes any of the above alkyl, aralkyl, or aryl groupslinked to a sulfur atom.

Unless otherwise indicated, the term “lower alkylamino,” “alkylamino,”“arylamino,” or “arylalkylamino” as employed herein alone or as part ofanother group includes any of the above alkyl, aryl, or arylalkyl groupslinked to a nitrogen atom.

As used herein, the term “heterocyclyl ” or “heterocyclic system” isintended to mean a stable 4- to 12-membered monocyclic or bicyclicheterocyclic ring which is saturated, or partially unsaturated, andwhich consists of carbon atoms and 1, 2, 3, or 4 heteroatomsindependently selected from the group consisting of N, NH, O, and S, andincluding any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized. The heterocyclic ring may beattached to its pendant group at any heteroatom or carbon atom whichresults in a stable structure. The heterocyclic rings described hereinmay be substituted on carbon or on a nitrogen atom if the resultingcompound is stable. If specifically noted, a nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another.

Unless otherwise indicated, the term “heteroaryl” as used herein aloneor as part of another group refers to a 5- or 12-membered aromatic ring,prefereably, a 5- or 6-membered aromatic ring, which includes 1, 2, 3,or 4 hetero atoms such as nitrogen, oxygen, or sulfur, and such ringsfused to an aryl, cycloalkyl, heteroaryl, or cycloheteroalkyl ring (e.g.benzothiophenyl, indolyl), and includes possible N-oxides. Theheteroaryl group may optionally include 1 to 4 substituents such as anyof the substituents set out above for alkyl. Examples of heteroarylgroups include the following:

and the like.

The term “heterocyclylalkyl” or “heterocyclyl” as used herein alone oras part of another group refers to heterocyclyl groups as defined abovelinked through a C atom or heteroatom to an alkyl chain.

The term “heteroarylalkyl” or “heteroarylalkenyl” as used herein aloneor as part of another group refers to a heteroaryl group as definedabove linked through a C atom or heteroatom to an alkyl chain, alkylene,or alkenylene as defined above.

The term “cyano” as used herein, refers to a —CN group.

The term “nitro” as used herein, refers to an —NO₂ group.

The term “hydroxy” as used herein, refers to an —OH group.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

Any compound that can be converted in vivo to provide the bioactiveagent (i.e., the compound of formula I) is a prodrug within the scopeand spirit of the invention.

The term “prodrugs” as employed herein includes phosphates, esters andcarbonates formed by reacting one or more hydroxyls of compounds offormula I with alkyl, alkoxy, or aryl substituted acylating orphosphorylating agents employing procedures known to those skilled inthe art to generate phosphates, acetates, pivalates, methylcarbonates,benzoates, and the like.

Various forms of prodrugs are well known in the art and are describedin:

-   -   a) The Practice of a Medicinal Chemistry, Camille G. Wermuth et        al., Ch. 31, (Academic Press, 1996);    -   b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985);    -   c) A Textbook of Drug Design and Development, P.        Krogsgaard-Larson and H. Bundgaard, eds. Ch. 5, pp. 113-191        (Harwood Academic Publishers, 1991); and    -   d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and        Joachim M. Mayer, (Wiley-VCH, 2003).        Said references are incorporated herein by reference.

In addition, compounds of the formula I are, subsequent to theirpreparation, preferably isolated and purified to obtain a compositioncontaining an amount by weight equal to or greater than 99% formula Icompound (“substantially pure” compound I), which is then used orformulated as described herein. Such “substantially pure” compounds ofthe formula I are also contemplated herein as part of the presentinvention.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The compounds of the present invention can have asymmetric centers atany of the carbon atoms including any one of the R substituents and/orexhibit polymorphism. Consequently, compounds of formula I can exist inenantiomeric, or diastereomeric forms, or in mixtures thereof. Theprocesses for preparation can utilize racemates, enantiomers, ordiastereomers as starting materials. When diastereomeric or enantiomericproducts are prepared, they can be separated by conventional methods forexample, chromatographic or fractional crystallization.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. The present invention is intended toembody stable compounds.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention alone or an amount of the combinationof compounds claimed or an amount of a compound of the present inventionin combination with other active ingredients effective to inhibit11beta-HSD1 or effective to treat or prevent diseases or disordersassociated with 11beta-HSD1.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

Synthesis

Compounds of formula I of may be prepared as shown in the followingreaction schemes and description thereof, as well as relevant literatureprocedures that may be used by one skilled in the art. Exemplaryreagents and procedures for these reactions appear hereinafter and inthe working Examples.

Preparing compounds of formula IA (a subset of compounds of formula I).A phenol intermediate II can be obtained commercially, prepared bymethods known in the literature or by other methods known to one skilledin the art. Formation of a compound IA can be carried out from a phenolII and an alcohol III using triphenylphosphine and DEAD or DIAD,commonly known as Mitsunobu Reaction. Alternatively, a compound IA canbe obtained from alkylation of a phenol II with a chloride IV or abromide V in the presence of an appropriate base, such as sodiumcarbonate or DIEA.

Scheme II describes a method for preparing compounds of formula IB andformula IC (subsets of compounds of formula I). A thiophenolintermediate VI can be obtained commercially, prepared by methods knownin the literature or by other methods known to one skilled in the art.Formation of a compound IB can be obtained from alkylation of athiophenol VI with a chloride IV or a bromide V in the presence of anappropriate base, such as sodium carbonate or DIEA. Subsequent oxidationof a compound 1B with an appropriate oxidizing reagent such as mCPBA,Oxone®, p-toluenesulfonic peracid generated in situ (Tetrahedron, 1996,52, 5773-5787) or by other reagents known to one skilled in the artprovides a compound 1C.

Scheme III describes a method for preparing compounds of formula ID (asubset of compounds of formula I). An arylsulfonyl chloride intermediateVII can be obtained commercially, prepared by methods known in theliterature or by other methods known to one skilled in the art.Formation of a compound ID can be achieved from the reaction of acompound of formula VII with an amine VIII in the presence of anappropriate base such as pyridine, DIEA or other reagents known to oneskilled in the art to provide a compound 1D.

Scheme IV describes a method for preparing compounds of formula IE (asubset of compounds of formula I). A phenol intermediate II can beobtained commercially, prepared by methods known in the literature or byother methods known to one skilled in the art. Formation of a compoundIE can be achieved from treatment of a potassium salt of a phenol II anda bromo- or iodo-substituted intermediate IX (G is Br or I) in thepresence of copper powder or salt at elevated temperature, commonlyknown as Ullmann Coupling Reaction (Tetrahedron, 1984, 40, 1433-1456).Alternatively, a compound IE can be obtained from a S_(N)AR reaction ofa phenol II and a bromo-, chloro- or fluoro-substituted intermediate IX(G is Br, Cl or F) in the presence of a base such as potassium hydride,sodium hydride, cesium carbonate, potassium carbonate at elevatedtemperature. Both Ullmann Coupling and S_(N)AR reactions can be carriedout under a conventional procedure or done in a microwave reactor.Furthermore, a compound IE can be obtained from a copperacetate-mediated aryl ether synthesis using a phenol II and anarylboronic acid X or a phenol XII and an arylboronic acid XI(Tetrahedron Lett., 1998, 39, 2937-2940).

Scheme V describes a method for preparing compounds of formula IF (asubset of compounds of formula I where Z is a 1,2,4-triazolopyridinegroup). A chloro- or fluropyridine intermediate XIII can be obtainedcommercially, prepared by methods known in the literature or by othermethods known to one skilled in the art. An appropriate protecting group(PG) may be used for an intermediate XIII (for example, a TBS group orether as a protecting group for an alcohol) for better functional groupcompatibility in the subsequent reaction. Reaction of a compound offormula XIII with hydrazine was carried out at elevated temperature toprovide an intermediate XIV. Acylation of an intermediate XIV with anacid XV using an appropriate set of amide coupling reagents suchNMM/isobutylchloformate, EDAC/HOBT or other reagents described in “ThePractice of Peptide Synthesis” (Spring-Verlag, 2^(nd) Ed., Bodanszy,Miklos, 1993) provides a hydrazide intermediate XVII. Alternatively, ahydrazide XVII can be prepared from the reaction of a compound offormula XIV and an acid chloride XVI in the presence of an appropriatebase such as DIEA or TEA. Formation of 1,2,4-triazolopyridine XVIII canbe achieved from the reaction of XVII with POCl₃ at an elevatedtemperature. Formation of 1,2,4-triazolopyridine XVIII can also beachieved from XVII in the presence of acetic acid at an elevatedtemperature, either under a conventional procedure or a microwavereactor. Alternatively, formation of 1,2,4-triazolopyridine XVIII can beachieved from the reaction of XVII with Ph₃PCl₂ in the presence of abase such as TEA or by other methods known to one skilled in the art.The protecting group, if present, can be removed from a compound offormula XVIII to provide an intermediate XIX (for more protecting groupexamples and conditions for their removal, see ‘Protective Groups inOrganic Synthesis’ Greene at al., John Wiley and Sons Inc., 1991).Formation of a compound of formula 1F can be achieved using reactionsdescribed in Schemes I to IV or by other methods known to one skilled inthe art.

Scheme VI describes a method for preparing compounds of formula IG (asubset of compounds of formula I where Z is a imidazo[1,2-a]pyridinegroup). An aminopyridine intermediate XX can be obtained commercially,prepared by methods known in the literature or by other methods known toone skilled in the art. An appropriate protecting group (PG) may be usedfor an intermediate XX (for example, a TBS group or ether as aprotecting group for an alcohol) for better functional groupcompatibility in the subsequent reactions. Reaction of a compound offormula XX with a bromide XXI provides an intermediate XXI, which, uponheating, yields an imidazonvridine intermediate XXIII (Heterocycles,2003, 59, 359-368). The protecting group, if present, can be removedfrom a compound of formula XXIII to provide an intermediate XXIV (formore protecting group examples and conditions for their removal, see‘Protective Groups in Organic Synthesis’ Greene at al., John Wiley andSons Inc., 1991). Formation of a compound 1G can be achieved usingreactions described in Schemes I to IV, or by other methods known to oneskilled in the art.

Scheme VII describes a method for preparing compounds of formula IH (asubset of compounds of formula I where Z is an imidazo[1,5-a]pyridinegroup). A cyano- or amidopyridine intermediate XXV can be obtainedcommercially, prepared by methods known in the literature or by othermethods Lowry to one skilled in the art. An appropriate protecting group(PG) may be used for an intermediate XXV (for example, a TBS group orether as a protecting group for an alcohol) for better functional groupcompatibility in the subsequent reaction. Reduction of the cyano oramide moiety in a compound of formula XXV may be carried out using anappropriate reducing reagent such as LAH or other reagents known to oneskilled in the art. Acylation of the resulting amine intermediate XXVIcan be performed by reacting it with an acid XV in the presence of a setof amide coupling reagents such as NMM/isobutylchloformate, EDAC/HOBT orother reagents described in “The Practice of Peptide Synthesis”(Spring-Verlag, 2^(nd) Ed., Bodanszy, Miklos, 1993), yielding an amideintermediate XXVII. Alternatively, an amide XXVII can be prepared fromthe reaction of a compound of formula XXVI and an acid chloride XVI inthe presence of an appropriate base such as DIEA or TEA. Formation ofimidazolopyridine XXVIII can be achieved from the reaction of XXVII withPOCl₃ at an elevated temperature. Alternatively, formation ofimidazolopyridine XXVIII can also be achieved from XXVII in the presenceof acetic acid at an elevated temperature, either under a conventionalprocedure or a microwave reactor. Furthermore, formation ofimidazolopyridine XXVIII can be achieved from the reaction of XXVII withPh₃PCl₂ in the presence of a base such as TEA or by other methods knownto one skilled in the art. The protecting group, if present, can beremoved from compound XXVIII to provide a compound of formula XXIX (formore protecting group examples and conditions for their removal, see‘Protective Groups in Organic Synthesis’ Greene at al., John Wiley andSons Inc., 1991). Formation of a compound 1H can be achieved usingreactions described in Schemes I to IV, or by other methods known to oneskilled in the art. In cases where R_(4a) is functional group such ascyano or aryl group, the compounds can be prepared via treatment ofcompound XXVIII to give a bromo intermediate (D. Davey, et al. J. Med.Chem. 1987, 30, 1337-1342) followed by Pd-catalyzed coupling reactions(H. G. Selnick, et al. Syn. Commun. 1995, 25, 3255-3261 and Suzuki, etal. Syn. Commun. 1981, 11, 513-519) to give compound XXVIII_A, or byother methods known to one skilled in the art. The protecting group, ifpresent, can be removed from compound XXVIII_A to provide a compound offormula XXIX_A (for more protecting group examples and conditions fortheir removal, see ‘Protective Groups in Organic Synthesis’ Greene atal., John Wiley and Sons Inc., 1991). Formation of a compound 1H can beachieved using reactions described in Schemes I to IV, or by othermethods known to one skilled in the art.

Scheme VIII describes a method for preparing compounds of formula IJ (asubset of compounds of formula I where Z is 1,2,3-triazolopyridinegroup). A bromopyridine intermediate XXX can be obtained commercially,prepared by methods known in the literature, or by other methods knownto one skilled in the art. An appropriate protecting group (PG) may beused for an intermediate XXX (for example, a TBS group or ether as aprotecting group for an alcohol) for better functional groupcompatibility in the subsequent reaction. Treatment of a compound offormula XXX with n-BuLi followed by addition of a compound XXXI providesa ketone intermediate XXXII. Formation of a 1,2,3-triazolopyridineXXXIII can be achieved by the reaction of a compound XXXII andbenzenesulfonohydrazide in the presence of morpholine (Tetrahedron,1997, 53, 8257-8268), or by other methods known to one skilled in theart. The protecting group, if present, can be removed from compoundXXXIII to provide a compound of formula XXXIV (for more protecting groupexamples and conditions of their removal, see ‘Protective Groups inOrganic Synthesis’ Greene at al., John Wiley and Sons Inc., 1991).Formation of a compound 1J can be achieved using reactions described inSchemes I to IV, or by other methods know to one skilled in the art.

Scheme IX describes a method for preparing compounds of formula IK (asubset of compounds of formula I where Z is benzotriazole group). Anintermediate XXXV can be obtained commercially, prepared by methodsknown in the literature, or by other methods known to one skilled in theart. An appropriate protecting group (PG) may be used for anintermediate XXXV (for example, a TBS group or ether as a protectinggroup for an alcohol) for better functional group compatibility in thesubsequent reactions. An intermediate XXXVII can be obtained from anucleophilic aromatic substitution reaction of a compound XXXV with anamine XXXVI at elevated temperature or by palladium-mediated N-arylation(J. Org. Chem., 2000, 65, 1144-1157), or by other methods known to oneskilled in the art. Reduction of the nitro group in a compound XXXVIIcan be carried out with appropriate reducing reagents such as hydrogenin the presence of a Pd—C catalyst or Zn dust in HCl to provide anintermediate XXXVIII. Treatment of a compound XXXVIII with sodiumnitrite in the presence of an acid provides a benzotriazole intermediateof formula XXXIX (J. Med. Chem., 1990, 33, 2343-2357). Alternatively, abenzotriazole intermediate XXXIX can be obtained from the reaction of ananiline XXXX and an azide XXXXI in the presence of3-methyl-1-nitrobutane (J. Chem. Soc. Perkin Trans. 1, 1985, 2733-2739).The protecting group, if present, can be removed from a compound XXXIXto provide a compound of formula XXXXII (for more protecting groupexamples and conditions for their removal, see ‘Protective Groups inOrganic Synthesis’ Greene at al., John Wiley and Sons Inc., 1991).Formation of a compound 1K can be achieved using reactions described inSchemes I to IV, or by other methods known to one skilled in the art.

Scheme X describes a method for preparing compounds of formula IL (asubset of compounds of formula I where Z is triazolopyridazine group).An intermediate of formula XXXXII can be obtained commercially, preparedby methods known in the literature, or by other methods known to oneskilled in the art. An appropriate protecting group (PG) may be used foran intermediate of formula XXXXIII (for example, a Cbz group as aprotecting group for an amine) for better functional group compatibilityin the subsequent reaction. Treatment of an intermediate XXXXIII withPOCl₃ provides a chloropyridazine intermediate XXXXIV. Reaction of acompound XXXXIV with hydrazine can be carried out at elevatedtemperature to provide an intermediate XXXXV. Acylation of anintermediate XXXXV with an acid XV using an appropriate set of amidecoupling reagents such NMM/isobutylchloformate, EDAC/HOBT or otherreagents described in “The Practice of Peptide Synthesis”(Spring-Verlag, 2^(nd) Ed., Bodanszy, Miklos, 1993) yields a hydrazideintermediate XXXXVI. Alternatively, a hydrazide XXXXVI can be preparedfrom the reaction of a compound XXXXV and an acid chloride XVI in thepresence of an appropriate base such as DIEA or TEA. Formation oftriazolopyridazine XXXXVII can be achieved from the reaction of XXXXVIwith POCl₃ at an elevated temperature. Alternatively, formation oftriazolopyridazine XXXXVII can also be achieved from XXXXVI in thepresence of acetic acid at an elevated temperature, either under aconventional procedure or a microwave reactor. Furthermore, formation oftriazolopyridazine XXXXVII can be achieved from the reaction of XXXXVIwith Ph₃PCl₂ in the presence of a base such as TEA or by other methodsknown to one skilled in the art. The protecting group, if present, canbe removed from a compound XXXXVII to provide an intermediate XXXXVIII(for more protecting group examples and conditions for their removal,see ‘Protective Groups in Organic Synthesis’ Greene at al., John Wileyand Sons Inc., 1991). Formation of a compound 1L can be achieved usingreactions described in Schemes I to IV, or by other methods known to oneskilled in the art.

An appropriate protecting group (PG) may be used for the intermediatecompounds and/or functional groups (for example R₁, R_(1a), R_(1b),R_(1c), R_(1d), R_(2a), R_(2b), R_(2c), R_(2d), R₃ R_(3a), R_(3b), R₄,and L) described in Schemes I-X for better reaction compatibility. Theprotecting group, if present, can be removed to provide desiredcompound. For more protecting group examples and conditions for theirremoval, see “Protective Groups in Organic Synthesis”, Greene at al.,John Wiley and Sons Inc., 1991.

Utilities and Combinations

A. Utilities

The compounds of the present invention possess activity as inhibitors ofthe enzyme 11-beta-hydroxysteroid dehydrogenase type I, and, therefore,may be used in the treatment of diseases associated with11-beta-hydroxysteroid dehydrogenase type I activity. Via the inhibitionof 11-beta-hydroxysteroid dehydrogenase type I, the compounds of thepresent invention may preferably be employed to inhibit or modulateglucocorticoid production, thereby interrupting or modulating cortisoneor cortisol production.

Accordingly, the compounds of the present invention can be administeredto mammals, preferably humans, for the treatment of a variety ofconditions and disorders, including, but not limited to, treating,preventing, or slowing the progression of diabetes and relatedconditions, microvascular complications associated with diabetes,macrovascular complications associated with diabetes, cardiovasculardiseases, Metabolic Syndrome and its component conditions, inflammatorydiseases and other maladies. Consequently, it is believed that thecompounds of the present invention may be used in preventing,inhibiting, or treating diabetes, hyperglycemia, impaired glucosetolerance, insulin resistance, hyperinsulinemia, retinopathy,neuropathy, nephropathy, delayed wound healing, atherosclerosis and itssequelae (acute coronary syndrome, myocardial infarction, anginapectoris, peripheral vascular disease, intermitant claudication),abnormal heart function, myocardial ischemia, stroke, MetabolicSyndrome, hypertension, obesity, dislipidemia, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL,non-cardiac ischemia, infection, cancer, vascular restenosis,pancreatitis, neurodegenerative disease, lipid disorders, cognitiveimpairment and dementia, bone disease, HIV protease associatedlipodystrophy, glaucoma and inflammatory diseases, such as, rheumatoidarthritis and osteoarthritis.

Metabolic Syndrome or “Syndrome X” is described in Ford, et al., J. Am.Med. Assoc. 2002, 287, 356-359 and Arbeeny, et al., Curr. Med. Chem.-Imm., Endoc. & Metab. Agents 2001, 1, 1-24.

B. Combinations

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of formula I, alone orin combination with a pharmaceutical carrier or diluent. Optionally,compounds of the present invention can be used alone, in combinationwith other compounds of the invention, or in combination with one ormore other therapeutic agent(s), e.g., an antidiabetic agent or otherpharmaceutically active material.

The compounds of the present invention may be employed in combinationwith other 11-beta-hydroxysteroid dehydrogenase type I inhibitors or oneor more other suitable therapeutic agents useful in the treatment of theaforementioned disorders including: anti-diabetic agents,anti-hyperglycemic agents, anti-hyperinsulinemic agents,anti-retinopathic agents, anti-neuropathic agents, anti-nephropathicagents, anti-atherosclerotic agents, anti-ischemic agents,anti-hypertensive agents, anti-obesity agents, anti-dislipidemic agents,anti-dylsipidemic agents, anti-hyperlipidemic agents,anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents,anti-restenotic agents, anti-pancreatic agents, lipid lowering agents,appetite suppressants, memory enhancing agents, cognition promotingagents and anti-inflammatory agents.

Examples of suitable anti-diabetic agents for use in combination withthe compounds of the present invention include insulin and insulinanalogs: LysPro insulin, inhaled formulations comprising insulin;glucagon-like peptides; sulfonylureas and analogs: chlorpropamide,glibenclamide, tolbutamide, tolazamide, acetohexamide, glypizide,glyburide, glimepiride, repaglinide, meglitinide; biguanides: metformin,phenformin, buformin; alpha2-antagonists and imidazolines: midaglizole,isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan; other insulinsecretagogues: linogliride, insulinotropin, exendin-4, BTS-67582,A-4166; thiazolidinediones: ciglitazone, pioglitazone, troglitazone,rosiglitazone; PPAR-gamma agonists; PPAR-alpha agonists; PPARalpha/gamma dual agonists; SGLT2 inhibitors; dipeptidyl peptidase-IV(DPP4) inhibitors; glucagon-like peptide-1 (GLP-1) receptor agonists;aldose reductase inhibitors; RXR agonists: JTT-501, MCC-555, MX-6054,DRF2593, GI-262570,-KR-P-297, LG100268; fatty acid oxidation inhibitors:clomoxir, etomoxir; α-glucosidase inhibitors: precose, acarbose,miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MDL-73,945;beta-agonists: BRL 35135, BRL 37344, Ro 16-8714, ICI D7114, CL 316,243,TAK-667, AZ40140; phosphodiesterase inhibitors, both cAMP and cGMP type:sildenafil, L686398: L-386,398; amylin antagonists: pramlintide, AC-137;lipoxygenase inhibitors: masoprocal; somatostatin analogs: BM-23014,seglitide, octreotide; glucagon antagonists: BAY 276-9955; insulinsignaling agonists, insulin mimetics, PTP1B inhibitors: L-783281,TER17411, TER17529; gluconeogenesis inhibitors: GP3034; somatostatinanalogs and antagonists; antilipolytic agents: nicotinic acid, acipimox,WAG 994; glucose transport stimulating agents: BM-130795; glucosesynthase kinase inhibitors: lithium chloride, CT98014, CT98023; andgalanin receptor agonists.

Other suitable thiazolidinediones include Mitsubishi's MCC-555(disclosed in U.S. Pat. No. 5,594,016), Glaxo-Wellcome's GL-262570,englitazone (CP-68722, Pfizer), or darglitazone (CP-86325, Pfizer,isaglitazone (MIT/J&J), JTT-501 (JPNT/P&U), L-895645 (Merck), R-119702(Sankyo/WL), NN-2344 (Dr. Reddy/NN), or YM-440 (Yamanouchi).

Suitable PPAR alpha/gamma dual agonists include AR-HO39242(Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (Kyorin Merck), aswell as those disclosed by Murakami et al, “A Novel Insulin SensitizerActs As a Coligand for Peroxisome Proliferation—Activated Receptor Alpha(PPAR alpha) and PPAR gamma; Effect of PPAR alpha Activation on AbnormalLipid Metabolism in Liver of Zucker Fatty Rats”, Diabetes 47, 1841-1847(1998), and WO 01/21602, the disclosure of which is incorporated hereinby reference, employing dosages as set out therein, which compoundsdesignated as preferred are preferred for use herein.

Suitable alpha2 antagonists also include those disclosed in WO 00/59506,employing dosages as set out herein.

Suitable SGLT2 inhibitors include T-1095, phlorizin, WAY-123783, andthose described in WO 01/27128.

Suitable DPP4 inhibitors include saxagliptan, sitagliptan, vildagliptan,and denagliptan.

Suitable aldose reductase inhibitors include those disclosed in WO

Suitable meglitinides include nateglinide (Novartis) or KAD1229(PFiKissei).

Examples of GLP-1 receptor agonists include Exenatide (Byetta™), NN2211(Liraglutide, Novo Nordisk), AVE0010 (Sanofi-Aventis), R1583(Roche/Ipsen), SUN E7001 (Daiichi/Santory), GSK-716155 (GSK/Human GenomeSciences) and Exendin-4 (PC-DAC™).

Other anti-diabetic agents that can be used in combination withcompounds of the invention include ergoset and D-chiroinositol.

Suitable anti-ischemic agents include, but are not limited to, thosedescribed in the Physician's Desk Reference and NHE inhibitors,including those disclosed in WO 99/43663.

Examples of suitable lipid lowering agents for use in combination withthe compounds of the present invention include one or more MTPinhibitors, HMG CoA reductase inhibitors, squalene synthetaseinhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenaseinhibitors, cholesterol absorption inhibitors, ileal Na⁺/bile acidcotransporter inhibitors, upregulators of LDL receptor activity, bileacid sequestrants, cholesterol ester transfer protein inhibitors (e.g.,CP-529414 (Pfizer)), and/or nicotinic acid and derivatives thereof.

MTP inhibitors which may be employed as described above include thosedisclosed in U.S. Pat. Nos. 5,595,872, 5,739,135, 5,712,279, 5,760,246,5,827,875, 5,885,983, and 5,962,440.

The HMG CoA reductase inhibitors which may be employed in combinationwith one or more compounds of formula I include mevastatin and relatedcompounds, as disclosed in U.S. Pat. No. 3,983,140, lovastatin,(mevinolin) and related compounds, as disclosed in U.S. Pat. No.4,231,938, pravastatin, and related compounds, such as disclosed in U.S.Pat. No. 4,346,227, simvastatin, and related compounds, as disclosed inU.S. Pat. Nos. 4,448,784 and 4,450,171. Other HMG CoA reductaseinhibitors which may be employed herein include, but are not limited to,fluvastatin, disclosed in U.S. Pat. No. 5,354,772; cerivastatin, asdisclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080; atorvastatin, asdisclosed in U.S. Pat. Nos. 4,681,893, 5,273,945, 5,385,929 and5,686,104; atavastatin (Nissan/Sankyo's nisvastatin (NK-104)), asdisclosed in U.S. Pat. No. 5,011,930; visastatin (Shionogi-Astra/Zeneca(ZD-4522)) as disclosed in U.S. Pat. No. 5,260,440.

Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin,atorvastatin, fluvastatin, cerivastatin, atavastatin, and ZD-4522.

The fibric acid derivatives which may be employed in combination withone or more compounds of formula I include fenofibrate, gemfibrozil,clofibrate, bezafibrate, ciprofibrate, clinofibrate, and the like,probucol, and related compounds, as disclosed in U.S. Pat. No.3,674,836, fenofibrate and gemfibrozil being preferred, bile acidsequestrants, such as cholestyramine, colestipol and DEAE-Sephadex(Secholex®, Policexide®), as well as lipostabil (Rhone-Poulenc), EisaiE-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402),tetrahydrolipstatin (THL), istigmastanylphosphorylcholine (SPC, Roche),aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulenederivative), melinamide (Sumitomo), Sandoz 58-035, American CyanamidCL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinicacid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin,poly(diallylmethylamine) derivatives, such as disclosed in U.S. Pat. No.4,759,923, quaternary amine poly(diallyldimethylammonium chloride) andionenes, such as disclosed in U.S. Pat. No. 4,027,009, and other knownserum cholesterol lowering agents.

The ACAT inhibitor which may be employed in combination with one or morecompounds of formula I include those disclosed in Drugs of the Future24, 9-15 (1999), (Avasimibe); “The ACAT inhibitor, Cl-1011 is effectivein the prevention and regression of aortic fatty streak area inhamsters”, Nicolosi et al, Atherosclerosis (Shannon, Irel). (1998),137(1), 77-85; “The pharmacological profile of FCE 27677: a novel ACATinhibitor with potent hypolipidemic activity mediated by selectivesuppression of the hepatic secretion of ApoB100-containing lipoprotein”,Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1), 16-30; “RP73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor”,Smith, C., et al, Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50; “ACATinhibitors: physiologic mechanisms for hypolipidemic andanti-atherosclerotic activities in experimental animals”, Krause et al,Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A.,Inflammation: Mediators Pathways (1995),173-98, Publisher: CRC, BocaRaton., Fla.; “ACAT inhibitors: potential anti-atherosclerotic agents”,Sliskovic et al, Curr. Med. Chem. (1994), 1(3), 204-25; “Inhibitors ofacyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemicagents. 6. The first water-soluble ACAT inhibitor with lipid-regulatingactivity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7.Development of a series of substitutedN-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureas with enhancedhypocholesterolemic activity”, Stout et al, Chemtracts: Org. Chem.(1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co. Ltd.).

The hypolipidemic agent may be an upregulator of LDL receptor activity,such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).

Examples of suitable cholesterol absorption inhibitors for use incombination with the compounds of the invention include ezetimibe(Zetia®).

Examples of suitable ileal Na⁺/bile acid cotransporter inhibitors foruse in combination with the compounds of the invention include compoundsas disclosed in Drugs of the Future, 24, 425-430 (1999).

The lipoxygenase inhibitors which may be employed in combination withone or more compounds of formula I include 15-lipoxygenase (15-LO)inhibitors, such as benzimidazole derivatives, as disclosed in WO97/12615, 15-LO inhibitors, as disclosed in WO 97/12613, isothiazolones,as disclosed in WO 96/38144, and 15-LO inhibitors, as disclosed bySendobry et al “Attenuation of diet-induced atherosclerosis in rabbitswith a highly selective 15-lipoxygenase inhibitor lacking significantantioxidant properties”, Brit. J. Pharmacology (1997) 120, 1199-1206,and Cornicelli et al, “15-Lipoxygenase and its Inhibition: A NovelTherapeutic Target for Vascular Disease”, Current Pharmaceutical Design,1999, 5, 11-20.

Examples of suitable anti-hypertensive agents for use in combinationwith the compounds of the present invention include beta adrenergicblockers, calcium channel blockers (L-type and T-type; e.g. diltiazem,verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g.,chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,furosemide, (e.g., aliskiren), ACE inhibitors (e.g., captopril,zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril,pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists(e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g.,sitaxsentan, atrsentan, and compounds disclosed in U.S. Pat. Nos.5,612,359 and 6,043,265), Dual ET/AII antagonist (e.g., compoundsdisclosed in WO 00/01389), neutral endopeptidase (NEP) inhibitors,vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilatand germopatrilat), and nitrates.

Examples of suitable anti-obesity agents for use in combination with thecompounds of the present invention include a cannabinoid receptor 1antagonist or inverse agonist, a beta 3 adrenergic agonist, a lipaseinhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroidreceptor beta drug, and/or an anorectic agent.

Cannabinoid receptor 1 antagonists and inverse agonists which may beoptionally employed in combination with compounds of the presentinvention include rimonabant, SLV 319, CP-945598 (Pfizer), SR-147778(Sanofi-Aventis), MK0364 (Merck) and those discussed in D. L. Hertzog,Expert Opin. Ther. Patents 2004, 14, 1435-1452.

The beta 3 adrenergic agonists which may be optionally employed incombination with compounds of the present invention include AJ9677(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer,) or otherknown beta 3 agonists, as disclosed in U.S. Pat. Nos. 5,541,204,5,770,615, 5,491,134, 5,776,983, and 5,488,064, with AJ9677, L750,355,and CP331648 being preferred.

Examples of lipase inhibitors which may be optionally employed incombination with compounds of the present invention include orlistat orATL-962 (Alizyme), with orlistat being preferred.

The serotonin (and dopoamine) reuptake inhibitor and/or modulator whichmay be optionally employed in combination with a compound of formula Imay be sibutramine, topiramate (Johnson & Johnson), APD-356 (Arena) oraxokine (Regeneron), with sibutramine and APD-356 being preferred.

Examples of thyroid receptor beta compounds which may be optionallyemployed in combination with compounds of the present invention includethyroid receptor ligands, such as those disclosed in WO97/21993 (U. CalSF), WO99/00353 (KaroBio), and WO00/039077 (KaroBio), with compounds ofthe KaroBio applications being preferred.

The anorectic agent which may be optionally employed in combination withcompounds of the present invention include dexamphetamine, phentermine,phenylpropanolamine, or mazindol, with dexamphetamine being preferred.

Other compounds that can be used in combination with the compounds ofthe present invention include CCK receptor agonists (e.g., SR-27895B);MCHR1 antagonist (e.g., GSK 856464); galanin receptor antagonists; MCR-4antagonists (e.g., HP-228); leptin or mimetics; urocortin mimetics, CRFantagonists, and CRF binding proteins (e.g., RU-486, urocortin).

Further, the compounds of the present invention may be used incombination with HIV protease inhibitors, including but not limited toReyataz® and Kaletra®.

Examples of suitable memory enhancing agents, anti-dementia agents, orcognition promoting agents for use in combination with the compounds ofthe present invention include, but are not limited to, donepezil,rivastigmine, galantamine, memantine, tacrine, metrifonate, muscarine,xanomelline, deprenyl and physostigmine.

Examples of suitable anti-inflammatory agents for use in combinationwith the compounds of the present invention include, but are not limitedto, prednisone, acetaminophen, aspirin, codeine, fentaynl, ibuprofen,indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, asteroidal analgesic, sufentanyl, sunlindac, interferon alpha,prednisolone, methylprednisolone, dexamethazone, flucatisone,betamethasone, hydrocortisone, and beclomethasone.

The aforementioned patents and patent applications are incorporatedherein by reference.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention may be used, for example, inthose amounts indicated in the Physician's Desk Reference, as in thepatents set out above, or as otherwise determined by one of ordinaryskill in the art.

The compounds of formula I can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such as inthe form of tablets, capsules, granules or powders; sublingually;bucally; parenterally, such as by subcutaneous, intravenous,intramuscular, or intrasternal injection, or infusion techniques (e.g.,as sterile injectable aqueous or non-aqueous solutions or suspensions);nasally, including administration to the nasal membranes, such as byinhalation spray; topically, such as in the form of a cream or ointment;or rectally such as in the form of suppositories; in dosage unitformulations containing non-toxic, pharmaceutically acceptable vehiclesor diluents.

In carrying out the method of the invention for treating diabetes andrelated diseases, a pharmaceutical composition will be employedcontaining the compounds of formula I, with or without otherantidiabetic agent(s) and/or antihyperlipidemic agent(s) and/or othertype therapeutic agents in association with a pharmaceutical vehicle ordiluent. The pharmaceutical composition can be formulated employingconventional solid or liquid vehicles or diluents and pharmaceuticaladditives of a type appropriate to the mode of desired administration,such as pharmaceutically acceptable carriers, excipients, binders, andthe like. The compounds can be administered to a mammalian patient,including humans, monkeys, dogs, etc. by an oral route, for example, inthe form of tablets, capsules, beads, granules or powders. The dose foradults is preferably between 1 and 2,000 mg per day, which can beadministered in a single dose or in the form of individual doses from1-4 times per day.

A typical capsule for oral administration contains compounds ofstructure I (250 mg), lactose (75 mg), and magnesium stearate (15 mg).The mixture is passed through a 60 mesh sieve and packed into a No. 1gelatin capsule.

A typical injectable preparation is produced by aseptically placing 250mg of compounds of structure I into a vial, aseptically freeze-dryingand sealing. For use, the contents of the vial are mixed with 2 mL ofphysiological saline, to produce an injectable preparation.

Assay(s) for 11-Beta-Hydroxysteroid Dehydrogenase Activity

The in vitro inhibition of recombinant human 11beta-HSD1 was determinedas follows.

Recombinant human 11beta-HSD1 was expressed stably in HEK 293 EBNAcells. Cells were grown in DMEM (high glucose) containing MEMnon-essential amino acids, L-glutamine, hygromycine B (200 ug/ml), andG418(200 ug/ml). The cell pellets were homogenized, and the microsomalfraction was obtained by differential centrifugation. 11beta-HSD1 overexpressed microsomes were used as the enzyme source for theScintillation Proximity Assay (SPA). The test compounds at the desiredconcentration were incubated at room temperature with 12.5 μg ofmicrosomal enzyme, 250 nM [³H]-cortisone, 500 μM NADPH, 50 mM MES, pH6.5, and 5 mM EDTA in 96-well OptiPlates. The reaction was terminatedwith the addition of 1 mM 18β-glycerrhentic acid. SPA reagent mixture(YSi anti-rabbit IgG, anti-cortisol antibody in 50 mM Tris, pH 8.0containing 1% CHAPS and 1% glycerol) was added and the reaction wasfurther incubated at room temperature over night and counted inTopCount. The IC₅₀ (concentration of compound required for 50%inhibition of cortisol formation) was determined using XLfit.

In general, preferred compounds of the present invention, such asparticular compounds disclosed in the following examples, have beenidentified to inhibit the catalytic activity of 11-beta-hydroxysteroiddehydrogenase type I at concentrations equivalent to, or more potentlythan, 10 μM, preferably 5 μM, more preferably 3 μM, therebydemonstrating compounds of the present invention as especially effectiveinhibitors of 11-beta-hydroxysteroid dehydrogenase type I. Potencies canbe calculated and expressed as either inhibition constants (Ki values)or as IC50 (inhibitory concentration 50%) values, and refer to activitymeasured employing the assay system described above.

EXAMPLES

The following working Examples serve to better illustrate, but notlimit, some of the preferred embodiments of the present invention.

General

The term HPLC refers to a Shimadzu high performance liquidchrtomatography with one of following methods:

-   -   Method A: YMC or Phenomenex C18 5 micron 4.6×50 mm column using        a 4 minute gradient of 0-100% solvent B [90% MeOH:10% H₂O:0.2%        H₃PO₄] and 100-0% solvent A [10% MeOH:90% H₂O:0.2% H₃PO₄] with 4        mL/min flow rate and a 1 min. hold, an ultra violet (UV)        detector set at 220 nm.    -   Method B: Phenomenex S5 ODS 4.6×30 mm column, gradient elution        0-100% B/A over 2 min (solvent A=10% MeOH/H₂O containing 0.1%        TFA, solvent B=90% MeOH/H₂O containing 0.1% TFA), flow rate 5        mL/min, UV detection at 220 nm.    -   Method C: YMC S7 ODS 3.0×50 mm column, gradient elution 0-100%        B/A over 2 min (solvent A=10% MeOH/H₂O containing 0.1% TFA,        solvent B=90% MeOH/H₂O containing 0.1% TFA), flow rate 5 mL/min,        UV detection at 220 nm.

The term prep HPLC refers to an automated Shimadzu HPLC system using amixture of solvent A (10% MeOH/90% H₂O/0.2% TFA) and solvent B (90%MeOH/10% H₂O/0.2% TFA). The preparative columns were packed with YMC orPhenomenex ODS C18 5 micron resin or equivalent.

Abbreviations

The following abbreviations are employed in the Examples and elsewhereherein:

-   Ph=phenyl-   Bn=benzyl-   i-Bu=iso-butyl-   Me=methyl-   Et=ethyl-   Pr=propyl-   Bu=butyl-   AIBN=2,2′-Azobisisobutyronitrile-   Boc or BOC=tert-butoxycarbonyl-   Cbz=carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl-   DCM=dichloromethane-   DEAD=Diethyl azodicarboxylate-   DIAD=Diisopropyl azodicarboxylate-   DIEA=N,N-diisopropylethylamine-   DMA=N,N-dimethylacetylamide-   DMF=N,N-dimethylformamide-   DMSO=dimethylsulfoxide-   EtOAc=ethyl acetate-   EDAC=3-ethyl-3′-(dimethylamino)propyl-carbodiimide hydrochloride (or    1-[(3-(dimethyl)amino)propyl])-3-ethylcarbodiimide hydrochloride)-   FMOC=fluorenylmethoxycarbonyl-   HOAc or AcOH=acetic acid-   HOAT=1-hydroxy-7-azabenzotriazole-   HOBT=1-hydroxybenzotriazole-   LAH=lithium aluminum hydride-   mCPBA=3-Chloroperoxybenzoic acid-   NMM=N-methyl morpholine-   NBS=N-Bromosuccinimide-   n-BuLi=n-butyllithium-   Oxone®=Monopersulfate-   Pd/C=palladium on carbon-   PtO₂=platinum oxide-   PyBOP reagent=benzotriazol-1-yloxy-tripyrrolidino phosphonium    hexafluorophosphate-   SOCl₂=Thionyl chloride-   TBAF=tetrabutylammonium fluoride-   TBS=tert-Butyldimethylsilyl-   TMS=trimethylsilyl-   TEA=triethylamine-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   equiv=equivalent(s)-   min=minute(s)-   h or hr=hour(s)-   L=liter-   mL=milliliter-   μL=microliter-   g=gram(s)-   mg=milligram(s)-   mol=mole(s)-   mmol=millimole(s)-   meq=milliequivalent-   RT=room temperature-   sat or sat'd=saturated-   aq.=aqueous-   TLC=thin layer chromatography-   HPLC=high performance liquid chromatography-   HPLC R_(t)=HPLC retention time-   LC/MS=high performance liquid chromatography/mass spectrometry-   MS or Mass Spec=mass spectrometry-   NMR=nuclear magnetic resonance-   mp=melting point

Example 13-Cycloheptyl-8-((2,6-dichlorophenoxy)methyl)H-imidazo[1,5-a]pyridine

Compound 1A: 3-(Bromomethyl)picolinonitrile

To a solution of 3-methylpicolinonitrile (660 mg, 5.6 mmol) in 20 mL ofcarbon tetrachloride was added NBS (1 g, 5.6 mmol) and dibenzoylperoxide (200 mg, 0.83 mmol) at RT. The reaction mixture was heated at80° C. for 2 hr, and then cooled to RT. The resulting solid was filteredoff, and the filtrate was concentrated under reduced pressure to providea residue. The residue was diluted with ethyl acetate, washed withwater, dried over Na₂SO₄ and concentrated under reduced pressure toprovide crude material. The crude material was purified via silica gelchromatography (10% ethyl acetate in hexanes) to provide compound 1A(510 mg, 46%) as a pale yellow oil. HPLC R_(t) (Method A): 1.72 min.LC/MS (m/z)=197 (M+H)⁺.

Compound 1B: 3-((2,6-Dichlorophenoxy)methyl)picolinonitrile

To a solution of 2,6-dichlorophenol (620 mg, 3.8 mmol) in 5 mL ofanhydrous acetone was added potassium carbonate (520 mg, 3.8 mmol) andcompound 1A (500 mg, 2.54 mmol) at RT. The reaction mixture was stirredat RT for 2 hr, and the resulting solid was filtered off. The solventwas removed from the filtrate in vacuo to provide a residue. The residuewas diluted with ethyl acetate, washed with water, dried over Na₂SO₄ andconcentrated to provide crude material. The crude material was purifiedvia silica gel chromatography using 10% ethyl acetate in hexanes toprovide compound 1B (530 mg, 50%) as a white solid. HPLC R_(t) (MethodA): 3.23 min. LC/MS (m/z)=279 (M+H)⁺ and 301 (M+Na)⁺.

Compound 1C: (3-((2,6-Dichlorophenoxy)methyl)pyridin-2-yl)methanamine

To a solution of compound 1B (500 mg, 1.8 mmol) in 4 mL of anhydrous THFwas added LAH (1.8 mL, 1.8 mmol, 1 M in THF) at −10° C. under nitrogen.The reaction mixture was stirred at 0° C. for 1 hr and quenched withwater. The THF was removed in vacuo, and the reaction mixture wasdiluted with ethyl acetate, washed with water, dried over Na₂SO₄, andconcentrated under reduced pressure to provide compound 1C (500 mg) as abrown oil. HPLC R_(t) (Method A): 2.43 min. LC/MS (m/z)=283 (M+H)⁺.

Compound 1D:N-((3-((2,6-Dichlorophenoxy)methyl)pyridin-2-yl)methyl)cycloheptane-carboxamide

To a solution of cycloheptanecarboxylic acid (255 mg, 1.8 mmol) in 3 mLof anhydrous THF was added NMM (0.24 mL, 2.2 mmol), followed by additionof iso-butyl chloroformate (0.285 mL, 2.2 mmol) at 0° C. under nitrogen.The reaction mixture was stirred at 0° C. for 30 min. After this time, asolution of compound 1C (500 mg, previous step) in 2 mL of THF wasadded. The resulting mixture was stirred at 0° C. for 30 min followed bystirring for 30 min at RT. The mixture was quenched with water, and thesolvent was removed in vacuo to yield a residue. The residue was dilutedwith ethyl acetate, washed with water, dried over Na₂SO₄ andconcentrated under reduced pressure to yield crude material. The crudematerial was purified via silica gel chromatography using 30% ethylacetate in hexanes to provide compound 1D (50 mg, 7%) as a yellow solid.HPLC R_(t) (Method A): 3.56 min. LC/MS (m/z)=407 (M+H)⁺.

Example 1

To a solution of compound 1D (50 mg, 0.12 mmol) in 2 mL of anhydroustoluene was added POCl₃ (23 μL, 0.25 mmol) at RT. The reaction mixturewas heated at 100° C. for 3 hr, cooled to RT and quenched with water.The reaction mixture was then diluted with ethyl acetate, washed withwater, dried over Na₂SO₄ and concentrated under reduced pressure toyield crude product. The crude product was purified via PrepHPLC toprovide Example 1 as a colorless oil (43 mg, 66%). HPLC R_(t) (MethodA): 3.00 min. LC/MS (m/z)=389 (M+H)⁺. ¹H NMR: δ 8.01 (s, 1H), 7.90 (d,J=7 Hz, 1H), 7.34 (d, J=8 Hz, 2H), 7.29 (d, J=7 Hz, 1H), 7.08 (t, J=8Hz, 1H), 7.02 (t, J=7 Hz, 1H), 5.17 (s, 2H), 3.39-3.50 (m, 1H),2.02-2.18 (m, 4H), 1.88-2.00 (m, 2H), 1.56-1.78 (m, 6H).

Example 23-Cycloheptyl-8-((2,6-dichlorophenoxy)methyl)H-imidazo[1,2-a]pyridine

Compound 2A: 2-Bromo-1-cycloheptylethanone

To a solution of cycloheptanecarboxylic acid (1.5 g, 10.5 mmol) in 5 mLof dichloromethane was added oxalyl chloride (10.5 mL, 21 mmol, 2 M indichloromethane), followed by addition of several drops of DMF at RT.The reaction mixture was stirred at RT for 1 hr, and then concentratedunder reduced pressure to yield an oil. The oil was dissolved in 10 mLof anhydrous THF. The resulting solution was cooled to 0° C. and asolution of trimethylsilyl diazomethane (6.8 mL, 13.6 mmol, 2 M indiethyl ether) was added at 0° C. Upon completion of addition, themixture was stirred at 0° C. overnight. At the conclusion of thisperiod, an 48% aqueous HBr solution (2.4 mL, 80.9 mmol) was added at 0°C., and the reaction mixture was stirred for 2 hr at 0° C. The reactionmixture was then quenched with 20% aqueous sodium carbonate. The solventwas removed in vacuo to yield a residue. The residue was diluted withethyl acetate, washed with water, dried over Na₂SO₄ and concentrated invacuo to yield the crude material. The crude material was purified viasilica gel chromatography using 5% ethyl acetate in hexanes to providecompound 2A (1 g, 43%) as a pale yellow oil. HPLC R_(t) (Method A): 3.27min. LC/MS (m/z)=219 (M+H)⁺ and 241 (M+Na)⁺.

Compound 2B: (3-CycloheptylH-imidazo[1,2-a]pyridin-8-yl)methanol

To a solution of (2-aminopyridin-3-yl)methanol (185 mg, 1.5 mmol) in 5mL of anhydrous ethanol was added compound 2A (250 mg, 1.1 mmol) at RT.The reaction mixture was heated at 80° C. for 10 hr, cooled to RT andthen concentrated under reduced pressure to yield a residue. The residuewas diluted with ethyl acetate, washed with water, dried over Na₂SO₄ andconcentrated to yield crude material. The crude material was purifiedvia silica gel chromatography using 30-50% ethyl acetate in hexanes toprovide compound 2B (160 mg, 57%) as a white solid. HPLC R_(t) (MethodA): 1.76 min. LC/MS (m/z)=245 (M+H)⁺.

Example 2

To a solution of compound 2B (73 mg, 0.3 mmol) in 2 mL of anhydrous THFwas added 2,6-dichlorophenol (98 mg, 0.6 mmol), triphenylphosphine (157mg, 0.6 mmol) and DEAD (105 mg, 0.6 mmol) at RT. The reaction mixturewas stirred at RT for 2 hr, and then concentrated under reducedpressure. The concentrated reaction mixture was diluted with ethylacetate, washed with water, dried over Na₂SO₄ and concentrated underreduced pressure to yield crude product. The crude product was purifiedvia silica gel chromatography using 30% ethyl acetate in hexanesfollowed by PrepHPLC to yield Example 2 as a pale-yellow oil (56 mg,37%). HPLC R_(t) (Method A): 3.00 min. LC/MS (m/z)=389 (M+H)⁺. ¹H NMR: δ8.25 (d, J=8 Hz, 1H), 8.20 (d, J=8 Hz, 1H), 7.46 (d, J=1 Hz, 1H), 7.35(t, J=8 Hz, 2H), 7.31 (d, J=8 Hz, 1H), 7.04 (t, J=8 Hz, 1H), 5.57 (s,2H), 3.15-3.25 (m, 1H), 2.08-2.18 (m, 2H), 1.50-1.80 (m, 10H).

Example 33-Cycloheptyl-7-((2,6-dichlorophenoxy)methyl)-[1,2,3]triazolo[1,5-a]pyridine

Compound 3A: (6-Bromopyridin-2-yl)(cycloheptyl)methanone

To a dry three-neck round bottom flask was added 30 mL of THF. The flaskwas cooled to −78° C., and n-butyllithium (16.9 mL, 42.2 mmol, 2.5 N inhexanes) was added to the flask in one portion. A solution of2,6-dibromopyridine (10 g, 42.2 mmol) in 70 mL of THF was slowly addedvia an addition funnel at −78° C. to provide a dark green solution. Uponcompletion of addition, the mixture was stirred for an additional 15 minat −78° C. To the dark green solution at −78° C. was added cycloheptylnitrile over 1 min. The reaction mixture was then warmed to RT. Once atthe prescribed temperature, a solution of 6N HCl (55 mL, 330 mmol) wasadded, and the reaction mixture was heated to reflux for 5 min, followedby stirring at RT for 30 min. The resulting solution was made basic byadding 1N NaOH at 0° C. The resulting mixture was extracted with ethylacetate, dried over MgSO₄ and concentrated to yield crude material. Thecrude material was purified via silica gel chromatography using 5% ethylacetate in hexanes to provide compound 3A (6.8 g, 57%) as a yellow oil.HPLC Rt (Method A): 4.09 min. LC/MS (m/z)=283 (M+H)⁺.

Compound 3B:(Z)-N′-((6-bromopyridin-2-yl)(cycloheptyl)methylene)4-methylbenzenesulfonohydrazide

To a solution of p-tolylsulfonhydrazide (3.7 g, 19.85 mmol) in 25 mL ofwarm methanol was added a solution of compound 3A (5.6 g, 19.85 mmol) in2 mL methanol. The mixture was swirled to ensure that it was homogenous.The reaction mixture was stirred at RT for 1h, heated at 50° C. for 2.5h, and then cooled to RT. To the reaction mixture was added 15 mL ofwater. The resulting mixture was warmed to about 60° C. effectdissolution. The compound 3B (7.5 g, 84%) was recrystallized from thesolution to give a white powder containing both the cis and the transisomers. HPLC R_(t) (Method A): 3.93, 4.03 min. LC/MS (m/z)=450 (M+H)⁺.

Compound 3C: 7-Bromo-3-cycloheptyl-[1,2,3]triazolo[1,5-a]pyridine

A solution of compound 3B (5.5 g, 12.21 mmol) was treated with 20 mL ofmorpholine at 95° C. for 40 min. The reaction mixture was concentratedunder reduced pressure and purified via silica gel chromatography using20% ethyl acetate in hexanes to provide compound 3C (710 mg, 20%) as acolorless oil. HPLC R_(t) (Method A): 3.47 min. LC/MS (m/z)=294 (M+H)⁺.

Compound 3D: Methyl3-cycloheptyl-[1,2,3]triazolo[1,5-a]pyridine-7-carboxylate

Compound 3C (270 mg, 0.92 mmol), palladium acetate (103 mg, 0.46 mmol),1,3-bis(diphenylphosphino)propane (152 mg, 0.368 mmol), DBU (168 mg,1.104 mmol), methanol (2.5 mL), and DMF (2.5 mL) were combined in asealed steel autoclave vessel. The autoclave vessel was then connectedto a carbon monoxide lecture bottle. The vessel was filled with carbonmonoxide gas to 70 psi, heated at 85° C. for 1.5 h, and then cooled toRT. The reaction mixture was then diluted with ethyl acetate. Theresulting solid was filtered off. The filtrate was washed with water,dried over with MgSO₄, and concentrated under reduced pressure to yieldcrude material. The crude material was purified via silica gelchromatography using 10-20% ethyl acetate in hexanes to provide compound3D (188 mg, 75%) as a colorless oil. HPLC R_(t) (Method A): 3.30 min.LC/MS (m/z)=274 (M+H)⁺.

Compound 3E: (3-Cycloheptyl-[1,2,3]triazolo[1,5-a]pyridin-7-yl)methanol

A solution of compound 3D (185 mg, 0.68 mmol) in 5 mL of methanol wastreated with NaBH₄ (154 mg, 4.06 mmol) at RT for 5 min. The reactionflask became hot. The reaction mixture was quenched with water and thenextracted with ethyl acetate. The ethyl acetate extract was dried overMgSO₄ and concentrated under reduced pressure to yield crude material.The crude material was purified via silica gel chromatography using20-50% ethyl acetate in hexanes to provide compound 3E (123 mg, 74%) asa white powder. HPLC R_(t) (Method A): 3.19 min. LC/MS (m/z)=246 (M+H)⁺.

Example 3

Example 3 (66 mg, 92%, white powder) was prepared from compound 3E in asimilar manner as described for the preparation of Example 2 fromcompound 2B. HPLC R_(t) (Method A): 4.26 min. LC/MS (m/z)=390 (M+H)⁺. ¹HNMR: δ 7.72 (d, J=8 Hz, 1H), 7.44 (d, J=1 Hz, 1H), 7.37 (d, J=8 Hz, 2H),7.26-7.32 (m, 1H), 7.10 (t, J=8 Hz, 1H), 5.68 (s, 2H), 3.30-3.40 (m,1H), 1.96-2.15 (m, 4H), 1.83-1.93 (m, 2H), 1.60-1.82 (m, 6H).

Example 41-Cycloheptyl-4-((2,6-dichlorophenoxy)methyl)-1H-benzo[d][1,2,3]triazole

Compound 4A: Azidocycloheptane

To a 250 mL round bottle flask containing cycloheptyl bromide (10 g,56.47 mmol) in 30 mL of THF was added trimethylsilyl azide (9.76 g, 84.7mmol), followed by addition of a solution of 1.0 N TBAF in THF (84.7 mL,84.7 mmol). The reaction mixture was heated at 70° C. for 6 h. Afterthis time, the solvent was removed under reduced pressure, and thereaction mixture was purified via silica gel chromatography usingpentane to provide compound 4A (7.10 g, 90%) as a colorless oil.

Compound 4B: 4-Chloro-1-cycloheptyl-1H-benzo[d][1,2,3]triazole

A solution of compound 4A (3.3 g, 23.4 mmol) and isoamyl nitrite (3.14mL, 23.4 mmol) in 80 mL of dichloroethane was heated to reflux, and asolution of 2-amino-3-chlorobenzoic acid (2g, 11.7 mmol) in 30 mL ofacetone was added dropwise in 2 h. Upon completion of addition, thereaction mixture was heated for another 2 h, and then cooled to RT. Thereaction mixture was then concentrated under reduced pressure to yield aresidue. The residue was partitioned between ethyl acetate and aqueous1N NaOH. The organic layer was separated, washed with 1N NaOH and water,dried over MgSO₄, and concentrated under reduced pressure to yield crudematerial. The crude material was purified via silica gel chromatographyusing 10-30% ethyl acetate in hexanes to provide compound 4B (0.6 g,21%) as a white powder. HPLC R_(t) (Method A): 3.48 min. LC/MS (m/z)=250(M+H)⁺.

Compound 4C: 1-Cycloheptyl-1H-benzo[d][1,2,3]triazole-4-carboxamide

Compound 4B (0.4 g, 1.60 mmol) and copper cyanide (0.43 g, 4.80 mmol)were suspended in 5 mL of wet 1-methyl-2-pyrrolidinone and heated at205° C. for 4 days in a sealed pressure tube. After the mixture wascooled to RT, water was added. The resulting powders were collected on afilter funnel, suspended in a mixture of solvents (methanol, chloroformand dichloromethane), and stirred overnight. The resulting mixture waspassed through a filter funnel, and the liquid portion was concentratedunder reduced pressure to provide crude material. The crude material waspurified via silica gel chromatography using 10-50% ethyl acetate inhexanes to provide compound 4C (0. 13 g, 34%) as a white powder. HPLCR_(t) (Method A): 3.08 min. LC/MS (m/z)=259 (M+H)⁺.

Compound 4D: 1-Cycloheptyl-1H-benzo[d][1,2,3]triazole4-carboxylic acid

To a stirred solution of compound 4C (40 mg, 0.155 mmol) in 1 mL of 75%sulfuric acid was added dropwise 0.5 mL of aqueous solution of sodiumnitrite (107 mg, 1.55 mmol) at 70° C. The reaction mixture was pouredinto 5 mL of ice water, filtered and dried under vacuum to providecompound 4D (38 mg, 95%) as a white powder. HPLC R_(t) (Method A): 3.00min. LC/MS (m/z)=260 (M+H)⁺.

Compound 4E: (1-Cycloheptyl-1H-benzo[d][1,2,3]triazol-4-yl)methanol

Compound 4D (14 mg, 0.054 nmol) was dissolved in 1.5 mL of THF andtreated with a solution of 2 N borane dimethylsulfide in THF (0.14 mL,0.27 mmol) at RT overnight. At the conclusion of this period, smallpieces of ice were added to the reaction mixture until all gas evolutionstopped. The reaction mixture was then stirred at RT for 3 h. After thistime, the reaction mixture was diluted with ethyl acetate., washed witha diluted bleach solution, dried over MgSO₄ and concentrated underreduced pressure to yield crude material. The crude material waspurified via silica gel chromatography using 5% methanol in ethylacetate to provide compound 4E (9 mg, 68%) as a colorless oil. HPLCR_(t) (Method A): 3.00 min. LC/MS (m/z)=246 (M+H)⁺.

Example 4

Example 4 (8.5 mg, 59%, white powder) was prepared from compound 4E in asimilar manner as described for the preparation of Example 2 fromcompound 2B. HPLC R_(t) (Method A): 4.22 min. LC/MS (m/z)=390 (M+H)⁺. ¹HNMR: δ 7.69 (dd, J=5, 3 Hz, 1H), 7.44-7.46 (m, 2H), 7.26 (d, J=8 Hz,2H), 6.95 (t, J=8 Hz, 1H), 5.65 (s, 2H), 4.79-4.91 (m, 1H), 2.08-2.32(m, 4H), 1.79-1.93 (m, 2H), 1.51-1.77 (m, 6H).

Examples 5 to 11

Examples 5 to 11 in Table 1 were synthesized according to the proceduresdescribed in Examples 1 to 4, or by other similar methods known to oneskilled in the art, with other appropriate reagents.

TABLE 1 Example Structure LC/MS Mass (M + H) HPLC purity (%) 5

407 95 6

392 97 7

390 96 8

406 97 9

376 98 10

392 98 11

301 95

1. A compound of formula (I)W-L-Z  (I) enantiomers, diastereomers, salts thereof wherein: W is aryl,which may be optionally substituted with R₁, R_(1a), R_(1b), R_(1c) andR_(1d); R₁, R_(1a), R_(1b), R_(1c) and R_(1d) are independentlyhydrogen, halogen, —OH, —CN, —NO₂, —CO₂R_(2a), —CONR₂R_(2a),—SO₂NR₂R_(2a), —SOR_(2a), —SO₂R_(2a), —NR₂SO₂R₆, —NR₂CO₂R₆, alkyl,haloalkyl, cycloalkyl, alkoxy, aryloxy, alkenyl, haloalkoxy, alkylthio,arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino,heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the aryl,heteroaryl or heterocyclyl may be optionally substituted with R₇,R_(7a), R_(7b), and R_(7c); or alternatively any two R₁, R_(1a), R_(1b),R_(1c) and R_(1d) can be taken together to form a fused aryl,heteroaryl, heterocyclyl ring or spiro heterocyclyl ring; L is O, S, SO,SO₂, alkenyl, cycloalkyl, NR₅, or CR₂R_(2a); R₂, R_(2a), R_(2b) andR_(2c) are independently hydrogen, halogen, alkyl or haloalkyl; oralternatively any two R₂, R_(2a), R_(2b), and R_(2c) can be takentogether to which the atom they are attached to form a cycloalkyl,halogen substituted cycloalkyl or heterocyclyl ring; Z is

R₃, R_(3a) and R_(3b) are independently hydrogen, halogen, —OH, —CN,—NO₂, —SO₂NR₂R_(2a), —SOR_(2a), SO₂R_(2a), —NR₂SO₂R₆, —NR₂CO₂R₆, alkyl,haloalkyl, cycloalkyl, alkoxy, aryloxy, alkenyl, haloalkoxy, alkylthio,arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino,heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the aryl,heteroaryl or heterocyclyl may be optionally substituted with R₇,R_(7a), R_(7b), and R_(7c); R₄ is bicyclo[2,2,2]octyl orbicyclo[2,2,1]heptyl, both of which may be optionally substituted withone or more substituents selected from halogen, —OH, —OR₆, —SR₆, —OCOR₆,—CN, —NR₅COR₆, —NR₅SO₂R₆, —COR₆, CO₂R₆, —CO₂H, —OCONR₂R_(2a),—CONR₂R_(2a), —NR₅CO₂R₆, —SO₂R₆, alkyl, alkoxy, aryl, amino,heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl, heteroarylor heterocyclyl may be optionally substituted with R₇, R_(7a), R_(7b),and R_(7c); or R₄ is cycloalkyl, other than bicyclo[2,2,2]octyl orbicyclo[2,2,1]heptyl, which may be optionally substituted with one ormore substituents selected from halogen, —OH, —OR₆, —SR₆, —OCOR₆, —CN,—NR₅COR₆, —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H, —OCONR₂R_(2a), —CONR₂R_(2a),—NR₅CO₂R₆, —SO₂R₆, alkyl, alkoxy, aryl, amino, heterocyclyl orheteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclylmay be optionally substituted with R₇, R_(7a), R_(7b), and R_(7c); or R₄is heterocyclyl, which may be optionally substituted with one or moresubstituents selected from halogen, —OH, —OR₆, —SR₆, —OCOR₆, —CN,—NR₅COR₆, —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H, —OCONR₂R_(2a), —CONR₂R_(2a),—NR₅CO₂R₆, —SO₂R₆, alkyl, alkoxy, aryl, amino, heterocyclyl orheteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclylmay be optionally substituted with R₇, R_(7a), R_(7b), and R_(7c); or R₄is alkyl, which may be optionally substituted with one or moresubstituents selected from halogen, —OH, —OR₆, —SR₆, —OCOR₆, —CN,—NR₅COR₆, —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H, —OCONR₂R_(2a), —CONR₂R_(2a),—NR₅CO₂R₆, —SO₂R₆, alkyl, alkoxy, aryl, amino, heterocyclyl orheteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclylmay be optionally substituted with R₇, R_(7a), R_(7b), and R_(7c);R_(4a) is hydrogen, CN, alkyl, haloalkyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl; R₅, at each occurrence, isindependently hydrogen, alkyl, cycloalkyl, aryl, haloalkyl, COR_(2a),CO₂R_(2a), SO₂NR₂R_(2a), or SO₂R_(2a); R₆, at each occurrence, isindependently alkyl, cycloalkyl, aryl or heteroaryl, all of which may beoptionally substituted with R₇, R_(7a), R_(7b), and R_(7c); and R₇,R_(7a), R_(7b), and R_(7c), at each occurrence, are independently halo,alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl, arylalkyl,arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy,amino, —OH, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy,heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio,arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino,arylcarbonylamino, —NO₂, —CN or thiol; excluding compounds having theformula:

wherein W is phenyl, said phenyl is optionally substituted with R₁,R_(1a), R_(1b), R_(1c) and R_(1d); R₁, R_(1a), R_(1b), and R_(1d) areindependently hydrogen, halogen, alkyl or haloalkyl; L is CH₂, O, S orSO₂; and R₄ is C₃₋₁₀cycloalkyl, other than bicyclo[2,2,2]octyl orbicyclo[2,2,1]heptyl, which may be optionally substituted with one ormore substituents selected from halogen, OH, CN, —NHCOR₆, —NHSO₂R₆,C₁₋₆alkyl, perhaloC₁₋₆alkyl, C₁₋₆alkoxy, perhaloC₁₋₆alkoxy,C₁₋₁₀heterocyclyl, C₁₋₁₀heteroaryl or phenyl; or R₄ isC₁₋₁₀heterocyclyl, which may be optionally substituted with one or moresubstituents selected from halogen, OH, CN, —NHCOR₆, —NHSO₂R₆,C₁₋₆alkyl, perhaloC₁₋₆alkyl, C₁₋₆alkoxy, perhaloC₁₋₆alkoxy,C₁₋₁₀heterocyclyl, C₁₋₁₀heteroaryl or phenyl; or R₄ is C₁₋₆alkyl, whichmay be optionally substituted with one or more substituents selectedfrom halogen, OH, CN, —NHCOR₆, —NHSO₂R₆, C₁₋₆alkyl, perhaloC₁₋₆alkyl,C₁₋₆alkoxy, perhaloC₁₋₆alkoxy, C₁₋₁₀heterocyclyl, C₁₋₁₀heteroaryl orphenyl.
 2. The compound of claim 1, wherein W is phenyl, which isoptionally substituted with R₁, R_(1a), R_(1b), R_(1c) and R_(1d). 3.The compound of claim 1, wherein: R₄ is bicyclo[2,2,2]octyl orbicyclo[2,2,1]heptyl, both of which may be optionally substituted withone or more substituents selected from halogen, —OH, —OR₆, —SR₆, —OCOR₆,—CN, —NR₅COR₆, —NR₅SO₂R₆, —COR₆, CO₂R₆, —CO₂H, —OCONR₂R_(2a),—CONR₂R_(2a), —NR₅CO₂R₆, —SO₂R₆alkyl, alkoxy, aryl, amino, heterocyclylor heteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl orheterocyclyl may be optionally substituted with R₇, R_(7a), R_(7b), andR_(7c); or R₄ is cycloalkyl, other than bicyclo[2,2,2]octyl orbicyclo[2,2,1]heptyl, which may be optionally substituted with one ormore substituents selected from halogen, —OH, —OR₆, SR₆, —OCOR₆, —CN,—NR₅COR₆, —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H, —OCONR₂R_(2a), CONR₂R_(2a),—NR₅CO₂R₆, —SO₂R₆, alkyl, alkoxy, aryl, amino, heterocyclyl orheteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclylmay be optionally substituted with R₇, R_(7a), R_(7b), and R_(7c); or R₄is heterocyclyl, which may be optionally substituted with one or moresubstituents selected from halogen, —OH, —OR₆, —SR₆, —OCOR₅, —CN,—NR₅COR₆, —NR₅SO₂R₆, —COR₆, —CO₂R₆, —CO₂H, —OCONR₂R_(2a), —CONR₂R_(2a),NR₅CO₂R₆, —SO₂R₆, alkyl, alkoxy, aryl, amino, heterocyclyl orheteroaryl, wherein the alkyl, alkoxy, aryl, heteroaryl or heterocyclylmay be optionally substituted with R₇, R_(7a), R_(7b), and R_(7c); R₅,at each occurrence, is independently hydrogen, alkyl, cycloalkyl, aryl,haloalkyl, COR_(2a), CO₂R_(2a), SO₂NR₂R_(2a), or SO₂R_(2a); R₆, at eachoccurrence, is independently alkyl, cycloalkyl, aryl or heteroaryl, allof which may be optionally substituted with R₇,R_(7a), R_(7b), andR_(7c); and R₇, R_(7a), R_(7b), and R_(7c), at each occurrence, areindependently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl,arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkyloxy, amino, —OH, hydroxyalkyl, acyl, heteroaryl,heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl,alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino,arylcarbonylamino, —NO₂, —CN or thiol.
 4. A compound of formula (I)W-L-Z  (I) enantiomers, diastereomers, salts thereof wherein: W is aryl,which may be optionally substituted with R₁, R_(1a), R_(1b), R_(1c), andR_(1d); R₁, R_(1a), R_(1b), R_(1c), and R_(1d) are independentlyhydrogen, halogen, —OH, —CN, —NO₂, —CO₂R_(2a), —CONR₂R_(2a),—SO₂NR₂R_(2a), —SOR_(2a), —SO₂R_(2a), —NR₂SO₂R₆, —NR₂CO₂R₆ alkyl,haloalkyl, cycloalkyl, alkoxy, aryloxy, alkenyl, haloalkoxy, alkylthio,arylthio, arylsulfonyl, alkylamino, aminoalkyl, arylamino,heteroarylamino, aryl, heteroaryl or heterocyclyl, wherein the aryl,heteroaryl or heterocyclyl may be optionally substituted with R₇,R_(7a), R_(7b), and R_(7c); or alternatively any two R₁, R_(1a), R_(1b),R_(1c) and R_(1d) can be taken together to form a fused aryl,heteroaryl, heterocyclyl ring or spiro heterocyclyl ring; L is O; R₂,R_(2a), R_(2b) and R_(2c) are independently hydrogen, halogen, alkyl orhaloalkyl; or alternatively any two R₂, R_(2a), R_(2b) and R_(2c) can betaken together to which the atom they are attached to form a cycloalkyl,halogen substituted cycloalkyl or heterocyclyl ring; Z is

R₃ R_(3a) and R_(3b) are independently hydrogen, halogen, —OH, —CN,—NO₂, —CO₂R_(2a), —CONR₂R_(2a), SO₂NR₂R_(2a), —SOR_(2a), SO₂R_(2a),—NR₂SO₂R₆, —NR₂CO₂R₆, alkyl, haloalkyl, cycloalkyl, alkoxy, aryloxy,alkenyl, haloalkoxy, alkylthio, arylthio, arylsulfonyl, alkylamino,aminoalkyl, arylamino, heteroarylamino, aryl, heteroaryl orheterocyclyl, wherein the aryl, heteroaryl or heterocyclyl may beoptionally substituted with R₇, R_(7a), R_(7b), and R_(7c); R₄ isbicyclo[2,2,2]octyl or bicyclo[2,2,1]heptyl, both of which may beoptionally substituted with one or more substituents selected fromhalogen, —OH, —OR₆, —SR₆, —OCOR₆, —CN, —NR₅COR₆, —NR₅SO₂R₆, —COR₆,—CO₂R₆, —CO₂H, —OCONR₂R_(2a), —CONR₂R_(2a), —NR₅CO₂R₆, —SO₂R₆, alkyl,alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl,alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substitutedwith R₇, R_(7a), R_(7b), and R_(7c); or R₄ is cycloalkyl, other thanbicyclo[2,2,2]octyl or bicyclo[2,2,1]heptyl, which may be optionallysubstituted with one or more substituents selected from halogen, —OH,—OR₆, —SR₆, —OCOR₆, —CN, —NR₅COR₆, NR₅SO₂R₆, —COR₆, —CO₂R_(6 , —CO) ₂H,—OCONR₂R_(2a), —CONR₂R_(2a), —NR₅CO₂R₆, SO₂R₆, alkyl, alkoxy, aryl,amino, heterocyclyl or heteroaryl, wherein the alkyl, alkoxy, aryl,heteroaryl or heterocyclyl may be optionally substituted with R₇,R_(7a), R_(7b), and R_(7c); or R₄is heterocyclyl, which may beoptionally substituted with one or more substituents selected fromhalogen, —OH, —OR₆, —SR₆, —OCOR₆, —CN, —NR₅COR₆, —NR₅SO₂R₆, —COR₆,—CO₂R₆, —CO₂H, —OCONR₂R_(2a), —CONR₂R_(2a), —NR₅CO₂R₆, —SO₂R₆, alkyl,alkoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl,alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substitutedwith R₇, R_(7a), R_(7b), and R_(7c); or R₄ is alkyl, which may beoptionally substituted with one or more substituents selected fromhalogen, —OH, —OR₆, —SR₆, —OCOR₆, —CN, —NR₅COR₆, —NR₅SO₂R₆, —COR₆,—CO₂R₆, —CO₂H, —OCONR₂R_(2a), —CONR₂R_(2a)—NR₅CO₂R₆, —SO₂R₆, alkyl,alikoxy, aryl, amino, heterocyclyl or heteroaryl, wherein the alkyl,alkoxy, aryl, heteroaryl or heterocyclyl may be optionally substitutedwith R₇, R_(7a), R_(7b), and R_(7c); R_(4a), is hydrogen, CN, alkyl,haloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;R₅, at each occurrence, is independently hydrogen, alkyl, cycloalkyl,aryl, haloalkyl, COR_(2a), CO₂R_(2a), SO₂NR₂R_(2a), or SO₂R_(2a); R₆ ateach occurrence, is independently alkyl, cycloalk aryl or heteroaryl,all of which may be optionally substituted with R₇, R_(7a), R_(7b), andR_(7c); and R₇, R_(7a), R_(7b), and R_(7c) , at each occurrence, areindependently halo, alkyl, haloalkyl, alkoxy, aryl, aryloxy, arylaryl,arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkyloxy, amino, —OH, hydroxyalkyl, acyl, heteroaryl,heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl,alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino,arylcarbonylamino, —NO₂, —CN or thiol; excluding compounds wherein: W isphenyl, said phenyl is optionally substituted with R₁, R_(1a), R_(1b),R_(1c) and R_(1d); R₁, R_(1a), R_(1b), R_(1c) and R_(1d) areindependently hydrogen, halogen, alkyl or haloalkyl; and R₄ isC₃₋₁₀cycloalkyl, other than bicyclo[2,2,2]octyl or bicyclo[2,2,1]heptyl,which may be optionally substituted with one or more substituentsselected from halogen, OH, CN, —NHCOR₆, —NHSO₂R₆, C₁₋₆alkyl,perhaloC₁₋₆alkyl, C₁₋₆alkoxy, perhaloC₁₋₆alkoxy, C₁₋₁₀heterocyclyl,C₁₋₁₀heteroaryl or phenyl; or R₄ is C₁₋₁₀heterocyclyl, which may beoptionally substituted with one or more substituents selected fromhalogen, OH, CN, —NHCOR₆, —NHSO₂R₆, C₁₋₆alkyl, perhaloC₁₋₆alkyl,C₁₋₆alkoxy, perhaloC₁₋₆alkoxy, C₁₋₁₀heterocyclyl, C₁₋₁₀heteroaryl orpheny; or R₄ is C₁₋₆alkyl, which may be optionally substituted with oneor more substituents selected from halogen, OH, CN, —NHCOR₆, —NHSO₂R₆,C₁₋₆alkyl, perhaloC₁₋₆alkyl, C₁₋₆alkoxy, perhaloC₁₋₆alkoxy,C₁₋₁₀heterocyclyl, C₁₋₁₀heteroaryl or phenyl.
 5. A compound,enantiomers, diastereomers, salts thereof, selected from the compoundshaving the following formula:


6. A pharmaceutical composition comprising a compound of claim
 1. 7. Thepharmaceutical composition of claim 6 further comprising apharmaceutically acceptable carrier.
 8. The pharmaceutical compositionof claim 6 further comprising at least one additional therapeutic agent.9. The pharmaceutical composition of claim 6, wherein the compound ofFormula (I) is present in a therapeutically effective amount.
 10. Apharmaceutical composition comprising a compound of claim
 4. 11. Thepharmaceutical composition of claim 10 further comprising apharmaceutically acceptable carrier.
 12. The pharmaceutical compositionof claim 10 further comprising at least one additional therapeuticagent.
 13. The pharmaceutical composition of claim 10, wherein thecompound of Formula (I) is present in a therapeutically effectiveamount.